Pharmaceutical combinations for treatment and prevention of neurodegenerative disorders

Abstract

Described herein in are methods of treating or preventing a condition in a subject in need thereof comprising administering to the subject a therapeutically-effective amount of a combination comprising a calcineurin inhibitor and an agent that is a CYP3A4 inducer and / or P-glycoprotein inhibitor. The condition may be a neurodegenerative disease or a risk of developing a neurodegenerative disease.

Description

Tarolli Ref. No. BU-034459 WO ORDW.S. Ref. No. 72797-7-1-601PHARMACEUTICAL COMBINATIONS FOR TREATMENT AND PREVENTION OF NEURODEGENERATIVE DISORDERSSTATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0001] This invention was made with government support under Grant Number R01 GM136906 awarded by the National Institutes of Health. The government has certain rights in the invention.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 790,812, filed April 18, 2025 which is incorporated herein by reference in its entirety.BACKGROUND

[0003] Over 55 million people worldwide have dementia, a group of brain disorders affecting memory, thinking, and the ability to perform daily activities. Symptoms of dementia usually first appear in mid 60s, progressively worsening. About 60-70% of dementia cases are caused by Alzheimer’s disease (AD). Around 7 million people in the United States have AD, a number expected to nearly double over the next 20 years. AD is characterized by progressive neurodegeneration pathologically defined by extracellular amyloid beta (A0) plaques, intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and neuronal loss and brain atrophy.SUMMARY

[0004] The present disclosure provides methods for treating a condition, e.g., a neurodegenerative disorder or disease, by administering combinations comprising a calcineurin inhibitor, e.g., tacrolimus or a pharmaceutically acceptable salt thereof, and a second agent.

[0005] In one aspect, described herein is a method of treating a condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that is (a) a CYP3A4 inducer; and / or (b) a P-glycoprotein (P-gp) inhibitor.

[0006] In one aspect, described herein is a method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i)tacrolimus, or a pharmaceutically acceptable salt thereof; and (ii) lumacaftor, or a pharmaceutically acceptable salt thereof.

[0007] In one aspect, described herein is a method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that exhibits calcineurin inhibitor-like properties.

[0008] In one aspect, described herein is a method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound, or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, described herein is a method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor or a pharmaceutically acceptable salt thereof; and (ii) a compound from Schedule A, or a pharmaceutically acceptable salt thereof.

[0010] In one aspect, described herein is a method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that (a) increases a therapeutic effect; (b) reduces systemic toxicity; (c) increases central nervous system concentration; and / or (d) reduces a therapeutically-effective dose of the calcineurin inhibitor or a pharmaceutically acceptable salt thereof.

[0011] In one aspect, described herein is a method of reducing systemic toxicity in a subject who is being treated with tacrolimus, or a pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, described herein is a method of decreasing a therapeutically-effective amount of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject who is receiving tacrolimus orthe pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0013] In one aspect, described herein is a method of increasing central nervous system concentration of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0014] In one aspect, described herein is a method of decreasing peripheral concentration of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.INCORPORATION BY REFERENCE

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE FIGURES

[0016] The present disclosure may be more readily understood by reference to the following drawings, wherein:

[0017] Figure 1 provides a schematic representation showing an overview of Z-LaP tracker methods: Zebrafish larvae are placed in a 100 pL well and shown a 3-hour presentation which includes visual and acoustic stimuli. A machine learning program, Z-LaP Tracker, measures the movements of the larvae, detecting 25 different behavioral parameters.

[0018] Figure 2 provides a table showing Z-LaP tracker behavioral parameters: The 25 behavioral measures calculated by Z-LaP Tracker for two doses of Lumacaftor, two doses of tacrolimus (FK506), and combinations of the two drugs, compared to DMSO. Dark gray highlighting indicates a >10% increase in the corresponding behavior, while light gray highlighting indicates a >10% decrease in the corresponding behavior.

[0019] Figure 3 provides a table showing Z-LaP tracker behavioral parameters: 23 behavioral measures calculated by Z-LaP Tracker for two doses of Lumacaftor (luma), two doses of CsA, and combinations of the two drugs, compared to DMSO. Dark gray highlighting indicates a >10% increase in the corresponding behavior, while light gray highlighting indicates a >10% decrease in the corresponding behavior.

[0020] Figure 4 provides graphs showing 3D activity plots of larval movement during Pl 5. These figures plot the movements of specific zebrafish larvae exposed to different treatments throughout a resting period during the Z-LaP Tracker presentation. The X and Y axes represent the coordinates of the zebrafish in the well, and the Z axis represents time. The shading of the plot indicates the speed of the larvae’s movements.

[0021] Figure 5 provides a graph showing the total response generated by each treatment in 7-LaP Tracker. Total response is calculated as the absolute sum of all Z-LaP Tracker behaviors. Coadministering tacrolimus with lumacaftor results in statistically significant synergy (error bars = SEM).

[0022] Figure 6 provides a schematic representation showing lumacaftor’ s activity in the calcineurin-NFAT pathway: Intracellular calcium activates calmodulin, binding calcineurin protein phosphatase. Calcineurin dephosphorylates NF AT, which promotes the transcription of inflammatory factors. Tacrolimus directly inhibits calcineurin, while lumacaftor indirectly inhibits calcineurin and decreases intracellular calcium levels.

[0023] Figure 7 provides images showing structure -based blind docking of lumacaftor with CNI targets: CB-DOCK2, a server for cavity detection-guided protein- ligand blind docking, revealed that lumacaftor has strong predicted interactions with targets of CNIs, including calcineurin, FKBP-12, and Cyclophilin A. A more negative Auto-Dock Vina Score (kcal / mol) predicts a greater binding affinity.

[0024] Figures 8A-8F provide images showing Ingenuity Pathway Analysis of lumacaftor and calcineurin inhibitors: Ingenuity Pathway Analysis reveals that FK506 (8 A) and CsA (8D) inhibit their downstream targets. Lumacaftor also demonstrates predicted activity inhibiting the targets of FK506 (8B) and CsA (8E). The greatest levels of predicted inhibition occur when both lumacaftor and FK506 (8C) or CsA (8F) are co-administered.DETAILED DESCRIPTION

[0025] Disclosed herein are methods of treating or preventing a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a combination disclosed herein.

[0026] Hyperactivity of the calcineurin-NFAT pathway has been linked to Alzheimer’s disease (AD) pathology, and calcineurin inhibitors (CNI) have been identified to reduce AD prevalence; yet their use is limited due to toxicity. Z-LaP Tracker, a deep neural network quantifying zebrafish behavior, can identify drugs producing a similar behavioral response to CNIs. As demonstrated herein, Z-LaP Tracker reveals that lumacaftor, a CFTR corrector FDA approved for cystic fibrosis, elicits a highly CNLlike response. Lumacaftor also synergizes to produce a greater magnitude response when combined with a CNI. Lumacaftor’ s CNI-like profile may be explained by lumacaftor’s inhibitory activity in the calcineurin-NFAT pathway. These results suggest that lumacaftor, especially in combination with a CNI, may provide a new treatment for AD, dementia, and other conditions.Combination Treatment

[0027] In one aspect, described herein is a method of administering to a subject a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a second agent. In one aspect, described herein is a method of treating or preventing a condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a second agent.1. Combinations of Calcineurin Inhibitor with an Agent that is a CYP3A4 Inducer and / or P-gp Inhibitor

[0028] In one aspect, described herein is a method of administering to a subject a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that is (a) a CYP3A4 inducer; and / or (b) a P-glycoprotein (P-gp) inhibitor. In one aspect, described herein is a method of treating or preventing a condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that is (a) a CYP3A4 inducer; and / or (b) a P-glycoprotein (P-gp) inhibitor. In some embodiments, the agent is a CYP3A4 inducer and a P-glycoprotein (P-gp) inhibitor.

[0029] In some embodiments, the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the agent, or the pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect. In some embodiments, the therapeutic effect is synergistic. In some embodiments, the therapeutic effect is additive.

[0030] In some embodiments, the CYP3A4 inducer increases CYP3A4 activity and / or increases CYP3A4 expression. In some embodiments, the P-gp inhibitor inhibits P-gp activity and / or decreases P-gp expression.

[0031] Calcineurin (CaN), also known as protein phosphatase 2 (PP2B), or protein phosphatase 3 (PPP3), is an enzyme that dephosphorylates serine and threonine residues in proteins. Calcineurin is widely expressed in many tissues, and acts on a large number of protein substrates when activated by increased levels of intracellular calcium in concert with calmodulin.

[0032] Calcineurin inhibitors (CNIs) are a class of compounds that inhibit the action of calcineurin. Calcineurin inhibitors (CNIs) can bind to cytoplasmic immunophilins to form complexes that inhibit calcineurin. Examples of immunophilin-binding calcineurin inhibitors are cyclosporine A (CsA) or its derivatives that bind to cyclophilins, tacrolimus (also known asFK506) or its derivative that bind to FK-binding proteins, voclosporin or its derivatives that bind to cyclophilin A, or pimecrolimus or its derivatives that bind to macrophilin-12 (FKBP-12). Other examples of calcineurin inhibitors are prednisolone, azathioprine, mycophenolate, belatacept, sirolimus, everolimus, INCA-6, etc.

[0033] In some embodiments, the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0034] In some embodiments, the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the agent that is a CYP3A4 inducer and / or a P-gp inhibitor is lumacaftor, or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the agent that is a CYP3A4 inducer and / or a P-gp inhibitor, is selected from a compound of Schedule A, or a pharmaceutically acceptable salt thereof.Schedule A.Acetaminophen Erdafitinib Methadone Prednisone Sunvozertinib Alpelisib Etoposide Mifepristone Progesterone Taletrectinib Asunaprevir Etravirine Mitapivat Quinine Tamoxifen Telotristat Cariprazine Geni stein Mitotane Relugolix ethyl Chlorpromazine Idelalisib Nifedipine Remibrutinib Terfenadine Clotrimazole Isavuconazole Norg estimate Repotrectinib Tesmilifene Daunorubicin Isavuconazonium Olaparib Reseipine Testosterone Testosterone Dexamethasone Ivosidenib Olutasidenib Rifamycin cypionate Dexamethasone Testosterone acetate Lansoprazole Omeprazole Rilpivirine enanthate Testosterone Elagolix Lenvatinib Paclitaxel Ritonavir undecanoate Enasidenib Levoketoconazole Pacritinib Sotagliflozin Tezacaftor Encorafenib Lumacaftor Pirtobrutinib Sparsentan Vemurafenib MedroxyprogesteroneEnzalutamide acetate Pralsetinib Stiripentol Vinblastine

[0037] In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are each administered orally (either together or separately). In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the agent (e.g., lumacaftor) is administered orally. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered orally and the agent (e.g., lumacaftor) is administered intravenously. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are each administered intravenously (either together or separately). In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are sequentially administered (e.g., the calcineurin inhibitor is administered at a time interval before the agent, or the agent is administered at a time interval before the calcineurin inhibitor). In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are concurrently administered. In some embodiments, the calcineurin inhibitor is administered once, twice, or three times a day. In some embodiments, the agent is administered once, twice, or three times a day.

[0038] In some embodiments, the calcineurin inhibitor is tacrolimus or a pharmaceutically acceptable salt thereof. In some embodiments, the agent that is (a) a CYP3A4 inducer; and / or (b) a P-glycoprotein (P-gp) inhibitor is lumacaftor or a pharmaceutically-acceptable salt thereof. Tacrolimus and lumacaftor can be administered in doses, dosing schedules and modes of administration as described herein.

[0039] In some embodiments, the administering results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0040] In some embodiments, the administering the combination results in increased central nervous system concentration of the calcineurin inhibitor. In some embodiments, the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent. In some embodiments, the central nervous system concentration of the calcineurininhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the administering results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent.

[0041] In some embodiments, decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0). In some embodiments, the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.2. Combinations of Tacrolimus and Lumacaftor

[0042] In one aspect, described herein is a method of administering to a subject a combination comprising: (i) tacrolimus, or a pharmaceutically acceptable salt thereof; and (ii) lumacaftor, or a pharmaceutically acceptable salt thereof. In some embodiments, described herein is a method of treating or preventing a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) tacrolimus, or a pharmaceutically acceptable salt thereof; and (ii) lumacaftor, or a pharmaceutically acceptable salt thereof.

[0043] Tacrolimus has a structure represented by the following formula:HO

[0044] Lumacaftor has the structure represented by the following formula:

[0045] Lumacaftor is a protein-folding chaperone approved in combination with ivacaftor to treat cystic fibrosis (CF). CF is an autosomal recessive disorder caused by a mutation in the CF transmembrane conductance regulator (CFTR) protein on chromosome 7. The CFTR protein is a channel facilitating the passive movement of chloride ions across the epithelial surface membrane. In CF, mutations in the CFTR impact chloride and bicarbonate transport, impairing mucus hydration and clearance. Lumacaftor promotes the correct folding of mutated CFTR, enabling it to function similarly to normal CFTR, ultimately enhancing delivery of the CFTR protein to the cell surface (Van Goor F, et al.. Proc Natl Acad Sci U S A. 2011 Nov 15; 108(46): 18843-8). Lumacaftor has a benign side effect profile and is approved for adults and children as young as one year of age.

[0046] In some embodiments, tacrolimus, or the pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect. In some embodiments, the therapeutic effect is synergistic. In some embodiments, the therapeutic effect is additive.

[0047] In some embodiments, tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are each administered orally. In some embodiments, tacrolimus, or a pharmaceutically acceptable salt thereof, is administered intravenously and lumacaftor, or a pharmaceutically acceptable salt thereof, is administered orally. In some embodiments, tacrolimus, or a pharmaceutically acceptable salt thereof, is administered orally and lumacaftor, or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments, tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are each administered intravenously. In someembodiments, tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are sequentially administered (e.g., tacrolimus is administered at a time interval before lumacaftor, or lumacaftor is administered at a time interval before tacrolimus). In some embodiments, tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are concurrently administered. In some embodiments, tacrolimus, or a pharmaceutically acceptable salt thereof, is administered once, twice, or three times a day. In some embodiments, lumacaftor, or a pharmaceutically acceptable salt thereof, is administered once, twice, or three times a day.

[0048] In some embodiments, the therapeutically effective amount of tacrolimus is about 0.075 mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses. In some embodiments, the therapeutically effective amount of tacrolimus is about 3 mg to about 25 mg administered in one or two daily doses. In some embodiments, the therapeutically effective amount is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses. In some embodiments, the therapeutically effective amount of lumacaftor is about 100 mg / day to about 800 mg / day administered in one or two daily doses.

[0049] In one aspect, described herein is a method of reducing systemic toxicity in a subject who is being treated with tacrolimus, or a pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor. In some embodiments, the therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor. In some embodiments, the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor. In some embodiments, the therapeutic dose of tacrolimus is (i) 0.15 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor. In some embodiments, the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor. In some embodiments, the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

[0051] In some embodiments, lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times greater than the second daily dose.

[0052] In some embodiments, the administering results in reduced systemic toxicity of tacrolimus or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered tacrolimus or the pharmaceutically acceptable salt thereof in absence of lumacaftor or the pharmaceutically acceptable salt thereof. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0053] In one aspect, described herein is a method of decreasing a therapeutically-effective amount of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject who is receiving tacrolimus or the pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof In some embodiments, the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered tacrolimus or the pharmaceutically acceptable salt thereof in absence of lumacaftor or the pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof. In some embodiments, the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof. In some embodiments, the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof. In some embodiments, the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the therapeutically-effective amount of tacrolimus, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of tacrolimus, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of lumacaftor, or the pharmaceutically acceptable salt thereof. In some embodiments, the exposure level of tacrolimus, or the pharmaceutically acceptable salt thereof, is higher in the subject when co-administered with lumacaftor, or a pharmaceutically acceptable salt thereof, compared to the exposure level of tacrolimus, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of lumacaftor, or the pharmaceutically acceptable salt thereof.

[0054] In one aspect, described herein is a method of increasing central nervous system concentration of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof. In some embodiments, the administering increases central nervous system concentration of tacrolimus, or the pharmaceutically acceptable salt thereof. In some embodiments, the central nervous system concentration of tacrolimus, or the pharmaceutically acceptable salt thereof, is higher compared to a control subject administered tacrolimus, or the pharmaceutically acceptable salt thereof, in absence of lumacaftor, or the pharmaceutically acceptable salt thereof. In some embodiments, the central nervous system concentration of tacrolimus, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0055] In one aspect, described herein is a method of decreasing peripheral concentration (e.g., plasma, blood or tissue concentration) of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof. In some embodiments, the administering results in decreased peripheral concentration of tacrolimus or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered tacrolimus or the pharmaceutically acceptable salt thereof, in absence of lumacaftor or the pharmaceutically acceptable salt thereof. In some embodiments, decreasing the peripheral concentration of tacrolimus, or the pharmaceutically acceptable salt thereof, in the subject reduces systemic toxicity in the subject. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0). In some embodiments, the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of tacrolimus, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.3. Combinations of Calcineurin Inhibitor with Agent that has Calcineurin-Like Properties

[0056] In another aspect, described herein is a method of administering to a subject a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that exhibits calcineurin inhibitor-like properties. In some embodiments, described herein is a method of treating or preventing a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that exhibits calcineurin inhibitorlike properties.

[0057] In some embodiments, the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the agent, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect. In some embodiments, the therapeutic effect is synergistic. In some embodiments, the therapeutic effect is additive.

[0058] In some embodiments, the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the agent that has calcineurin-like properties is lumacaftor, or a pharmaceutically acceptable salt thereof. Without wishing to be bound by theory, it has been discovered that lumacaftor further exhibits mechanistic and / or functional similarities to calcineurin inhibitors, e.g., cyclosporine A (CsA), tacrolimus (FK506) or pimecrolimus, and inhibits the action of calcineurin, while devoid of the toxicity exhibited by these CNIs. The inhibitory effects of lumacaftor may be attributed to binding to and inhibiting direct targets of CNIs, e.g., calcineurin, cyclophilin A, and / or FKBP-12.

[0060] Tacrolimus and lumacaftor can be administered in doses, dosing schedules and modes of administration as described above. In some embodiments, the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0061] In some embodiments, the agent that has calcineurin-like properties is a compound from Schedule A, or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, administering the combination results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0063] In some embodiments, administering the combination results in increased central nervous system concentration of the calcineurin inhibitor. In some embodiments, the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof. In some embodiments, the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0064] In some embodiments, administering the combination results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof. In some embodiments, decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0). In some embodiments, administering the combination decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.4. Combinations of Calcineurin Inhibitor with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulating Compound

[0065] In one aspect, described herein is method of administering to a subject a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound, or a pharmaceutically acceptable salt thereof. In some embodiments, described herein is method of treating or preventing a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound, or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, described herein are methods of treating or preventing or preventing a neurodegenerative disease in a subject, comprising administering a therapeutically effective amount of a combination of a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound and a calcineurin inhibitor to the subject.

[0067] In some embodiments, the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the CFTR modulating compound, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect. In some embodiments, the therapeutic effect is synergistic. In some embodiments, the therapeutic effect is additive.

[0068] In some embodiments, described herein is a combination of a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound and a calcineurin inhibitor. CFTR modulators are a class of compounds that act by improving production, intracellular processing, and / or function of the defective CFTR protein. CFTR modulators generally target the production or function of the mutant CFTR protein.

[0069] In some embodiments, CFTR modulators can be CFTR potentiators. CFTR potentiators facilitate the opening of ion channel on the cell surface to allow chloride and sodium (salt) to move in and out of the cell through the cell membrane, such as ivacaftor, deutivacaftor, dirocaftor (PTI-808); navocaftor (ABBV-3067); (S)-3-amino-N-(2-hydroxypropyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinamide (GLPG2451); N-(3-carbamoyl-5, 5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-3-carboxamide (GLPG1837, ABBV-974); (S)-3-amino-N-(2-hydroxypropyl)-5-((4- (trifluoromethoxy)phenyl)sulfonyl)picolinamide (Bardin E, et al., Eur J Med Chem. 2021 Mar 5;213: 113195); icenticaftor (QBW251); (l,2,4)triazolo(l,5-a)pyridin-2-amine,6-(phenylsulfonyl)-n-((4-(2-pyridinyl)phenyl)methyl)-6-(phenylsulfonyl)-n-((4-(2-pyridinyl)phenyl)methyl)(l,2,4)triazolo(l,5-a)pyridin-2-amine (FDL176) (Lopes-Pacheco M.Front Pharmacol. 2020 Feb 21 ;10:1662); ABBV-191 (Benden C, et al., Pulm Ther. 2021 Dec;7(2):377-393), or genistein.

[0070] In some embodiments, CFTR modulators can be CFTR correctors. CFTR correctors help the CFTR protein to form the right 3-D shape so that it is able to move to the cell surface, such as lumacaftor, tezacaftor, elexacaftor, VX-152 (Vertex); olacaftor (VX-440); bamocaftor (VX-659); 3-cyclobutyl-n-((dimethylamino)sulfonyl)-l-(4-fluorophenyl)-4-(4-methoxy(l,4'-bipiperidin)-r-yl)-lh-pyrazolo(3,4-b)pyridine-6-carboxamide (GLPG-2737); GLPG-3221; galicaftor (GLPG-2222); or posenacaftor (PTI-801) (Bardin E, et al., Eur J Med Chem. 2021 Mar 5;213: 113195); GLPG2851 (Lopes-Pacheco M. Front Pharmacol. 2020 Feb 21:10:1662), GLPG2665 (Cholon DM, et al., Expert Rev Precis Med Drug Dev. 2016;l(3):235-243), or 2-(7-ethoxy-4-(3-fluorophenyl)-l-oxophthalazin-2(lH)-yl)-N-methyl-N-(2-methylbenzo(D)oxazol-6-yl)acetamide (FDL-169) (Chemical Abstracts Service (CAS) Number: 1628416-28-3), FDL304 or FDL2052160 (Ghelani DP, et al., ACS Pharmacol Transl Sci. 2019 Oct 2;3(l):4-10). In other embodiments, CFTR modulators can be a dual-acting compound having activities of a corrector and a potentiator, such as trimethylangelicin and its derivatives. Some CFTR modulator therapies can be a combination of CFTR potentiators and CFTR correctors, such as Alyftrek (vanzacaftor / tezacaftor / deutivacaftor), Trikafta (elexacaftor / tezacaftor / ivacaftor), Symdeko (tezacaftor / ivacaftor), or Orkambi (lumacaftor / ivacaftor).

[0071] In some embodiment, the CFTR modulator is lumacaftor. As a CFTR corrector, lumacaftor acts as a chaperone during protein folding and increases the number of CFTR proteins that are trafficked to the cell surface. Lumacaftor may also be provided as a pharmaceutically acceptable salt form.

[0072] In some embodiments, the CFTR modulator is a compound of Schedule B:Schedule B: lumacaftor, vanzacaftor, tezacaftor, deutivacaftor, elexacaftor, ivacaftor, ataluren, cavosonstat, nesolicaftor, posenacaftor, dirocaftor, riociguat, gentamicin, genistein, olacaftor, bamocaftor, VX-828, 4-Cyclohexyloxy-2-{ l-[4-(4-methoxy-benzensulfonyl)-piperazin-l-yl]-ethylj-quinazoline, 4-methyl-2-(5-phenyl-lH-pyrazol-3-yl)phenol, l-(benzo[d][l,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)(3-hydroxypyrrolidin-l-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide, icenticaftor, galifactor, 3-cyclobutyl-N-(N,N-dimethylsulfamoyl)-l-(4-fluorophenyl)-4-(4-methoxy-[l,4,-bipiperidin]-r-yl)-lH-pyrazolo[3,4-b]pyridine-6-carboxamide, navocaftor, (2S,3R,4S,5S)-3-tert-Butyl-4-{ [2-methoxy-5-(trifhioromethyl)pyridin-3-yl]methoxy }-5-(2-methylphenyl)-l-[(2S)-oxane-2-carbonyl]pyrrolidine-2-carboxylic acid, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-3-carboxamide, (S)-3-amino-N-(2-hydroxypropyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinamide, or N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-lH-pyrazole-3-carboxamide, (S)-3-amino-N-(2-hydroxypropyl)-5-((4-(trifluoromethoxy)phenyl)sulfonyl)picolinamide, exaluren, 2-(7-ethoxy-4-(3-fluorophenyl)-l-oxophthalazin-2(lH)-yl)-N-methyl-N-(2-methylbenzo(D)oxazol-6-yl)acetamide, nesolicaftor, icenticaftor, phenylglycine-01, sulfonamide-01, (S)-l-(3-amino-6-(hydroxymethyl)-lH-indazol-l-yl)-3-(4-fluorophenoxy)-2-methylpropan-l-one, arylsulfonamide-pyrrolopyridine, (4bS,7S,8aR)-4b-benzyl-7-hydroxy-N-((2-methylpyridin-3-yl)methyl)-7-(3,3,3-trifluoropropyl)-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide, or ( l,2,4)triazolo(l ,5-a)pyridin-2-amine,6-(phenylsulfonyl)-n-((4-(2-pyridinyl)phenyl)methyl)-6-(phenylsulfonyl)-n-((4-(2-pyridinyl)phenyl)methyl)(l,2,4)triazolo(l,5-a)pyridin-2-amine, or a pharmaceutically acceptable-salt thereof.

[0073] In some embodiments, the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, is a CFTR potentiator, corrector, dual-acting potentiator and corrector, or a combination thereof. In some embodiments, the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, is a CFTR corrector. In some embodiments, the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, comprises calcineurin inhibitor-like activity.

[0074] In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g., lumacaftor) are each administered orally. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the CFTR modulating compound (e.g., lumacaftor) is administered orally. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered orally and CFTR modulating compound is administered intravenously. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g., lumacaftor) are each administered intravenously. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g., lumacaftor) are sequentially administered. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g., lumacaftor) are concurrently administered. In some embodiments, the calcineurin inhibitor is administered once, twice, or three times a day. In some embodiments, the CFTR modulating compound is administered once, twice, or three times a day.

[0075] In some embodiments, the calcineurin inhibitor is tacrolimus or a pharmaceutically acceptable salt thereof, and the CFTR modulator is lumacaftor or a pharmaceutically acceptable salt thereof. Tacrolimus and lumacaftor can be administered in doses, dosing schedules and modes of administration as described above. In some embodiments, the therapeutic dose of tacrolimus islower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0076] In some embodiments, administering the combination results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the CFTR modulating compound. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0077] In some embodiments, administering the combination results in increased central nervous system concentration of the calcineurin inhibitor. In some embodiments, the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the CFTR modulating compound. In some embodiments, the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0078] In some embodiments, administering the combination results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the CFTR modulating compound. In some embodiments, decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common TerminologyCriteria for Adverse Events v6.0 (CTCAE v6.0). In some embodiments, administering the combination decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0079] In some embodiments, described herein is a method of treating or preventing a condition, e.g., a neurodegenerative disease in a subject, comprising administering a therapeutically effective amount of a combination of a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound and a calcineurin inhibitor to the subject. A neurodegenerative disease is a neurological disorder caused by the progressive loss of neurons, in the process known as neurodegeneration, in the central nervous system (CNS) or peripheral nervous system (PNS). Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, prion diseases, etc. In some embodiments, the neurodegenerative disease is Alzheimer's disease. Alzheimer’s disease is a brain disorder that slowly destroys memory and thinking skills, and eventually, the ability to carry out the simplest tasks. In some embodiments, the neurodegenerative disease is Parkinson's disease. Parkinson's disease can affect both motor and non-motor systems. Symptoms usually develop gradually, with non-motor issues becoming more apparent as the disease progresses. Motor symptoms include tremors, bradykinesia (slow movement), and postural instability (i.e., difficulty maintaining balance). Non-motor symptoms develop later in the disease and include behavioral changes, cognitive impairment, depression, dysautonomia, etc. In other embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. ALS is a neurological disorder that affects motor neurons, the nerve cells in the brain and spinal cord that control voluntary muscle movement and breathing. Methods of treating or preventing a neurodegenerative disease by administering a therapeutically effective combination of CFTR modulating compound and a calcineurin inhibitor include simultaneous administration, or administration of CFTR modulator close in time to the administration of calcineurin inhibitor.5. Combinations of Calcineurin Inhibitor with Compounds of Schedule A or Schedule B

[0080] In one aspect, described herein is a method of administering to a subject a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a compound from Schedule A, or a pharmaceutically acceptable salt thereof. In some embodiments,described herein is a method of treating or preventing a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a compound from Schedule A, or a pharmaceutically acceptable salt thereof.

[0081] In one aspect, described herein is a method of administering to a subject a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a compound from Schedule B or a pharmaceutically acceptable salt thereof. In some embodiments, described herein is a method of treating or preventing a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) a compound from Schedule B or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the calcineurin inhibitor or the pharmaceutically acceptable salt thereof, and the compound from Schedule A or B, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect. In some embodiments, the therapeutic effect is synergistic. In some embodiments, the therapeutic effect is additive. In some embodiments, the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound from Schedule A or B is lumacaftor, or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the compound from Schedule A or B (e.g., lumacaftor) are each administered orally. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the compound from Schedule B (e.g., lumacaftor) is administered orally. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered orally and the compound from Schedule B is administered intravenously. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the compound from Schedule B (e.g., lumacaftor) are each administered intravenously. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the compound from Schedule B (e.g., lumacaftor) are sequentially administered. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the compound from Schedule B (e.g., lumacaftor) are concurrently administered. In some embodiments, the calcineurin inhibitor is administered once, twice, or three times a day. In some embodiments, the compound from Schedule B is administered once, twice, or three times a day.

[0084] In some embodiments, the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0085] In some embodiments, the calcineurin inhibitor is tacrolimus or a pharmaceutically acceptable salt thereof, and the compound from Schedule B is lumacaftor or a pharmaceutically acceptable salt thereof. Tacrolimus and lumacaftor can be administered in doses, dosing schedules and modes of administration as described above. In some embodiments, the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0086] In some embodiments, administering the combination results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the compound from Schedule A or B. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0087] In some embodiments, the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the compound from Schedule A or B. In some embodiments, the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof. In some embodiments, the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof. In some embodiments, the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof. In some embodiments, the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the compound from Schedule A or B. In some embodiments, the central exposure level of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is higher in the subject when co-administered with the compound from Schedule A or B, comparedto the exposure level of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the compound from Schedule A or B.

[0088] In some embodiments, administering the combination results in increased central nervous system concentration of the calcineurin inhibitor. In some embodiments, the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the compound from Schedule A or B. In some embodiments, the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0089] In some embodiments, administering the combination results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the compound from Schedule A or B. In some embodiments, decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0). In some embodiments, administering the combination decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.6. Combinations of Calcineurin Inhibitor with an Agent that (a) increases a therapeutic effect; (b) reduces systemic toxicity; (c) increases central nervous system concentration; and / or (d) reduces a therapeutically-ejfective dose of the calcineurin inhibitor

[0090] In one aspect, disclosed herein is a method of administering to a subject a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that (a) increases a therapeutic effect; (b)reduces systemic toxicity; (c) increases central nervous system concentration; and / or (d) reduces a therapeutically-effective dose; of the calcineurin inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is a method of treating or preventing a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising: (i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and (ii) an agent, or a pharmaceutically acceptable salt thereof, that (a) increases a therapeutic effect; (b) reduces systemic toxicity; (c) increases central nervous system concentration; and / or (d) reduces a therapeutically-effective dose; of the calcineurin inhibitor or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the agent, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect. In some embodiments, the therapeutic effect is synergistic. In some embodiments, the therapeutic effect is additive.

[0092] In some embodiments, the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof. In some embodiments, the agent, or the pharmaceutically acceptable salt thereof, is a compound selected from Schedule A or B. In some embodiments, the agent is lumacaftor, or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are each administered orally. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the agent (e.g., lumacaftor) is administered orally. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) is administered orally and the agent (e.g., lumacaftor) is administered intravenously. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are each administered intravenously. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are sequentially administered. In some embodiments, the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are concurrently administered. In some embodiments, the calcineurin inhibitor is administered once, twice, or three times a day. In some embodiments, the agent is administered once, twice, or three times a day.

[0094] In some embodiments, the calcineurin inhibitor is tacrolimus or a pharmaceutically acceptable salt thereof, and the agent is lumacaftor or a pharmaceutically acceptable salt thereof. Tacrolimus and lumacaftor can be administered in doses, dosing schedules and modes of administration as described above. In some embodiments, the therapeutic dose of tacrolimus islower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0095] In some embodiments, administering the combination results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0096] In some embodiments, administering the combination results in increased central nervous system concentration of the calcineurin inhibitor. In some embodiments, the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof. In some embodiments, the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0097] In some embodiments, administering the combination results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof. In some embodiments, decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject. In some embodiments, the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof. In some embodiments, the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, thesystemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0). In some embodiments, administering the combination decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.Methods of Treatment

[0098] Described herein are methods of treating or preventing a condition comprising administering to a subject in need thereof a therapeutically-effective amount of a combination disclosed herein.

[0099] In some embodiments, the condition is cognitive impairment. In some embodiments, the condition is mild, moderate, or severe cognitive impairment. In some embodiments, the condition is mild cognitive impairment. In some embodiments, the condition is a neurodegenerative disease. In some embodiments, the condition is a disease precursor or condition that predisposes the subject to develop a neurodegenerative disease. In some embodiments, the neurodegenerative disease selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease, Huntington’s disease, vascular disease dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, tangle-predominant senile dementia, Pick's disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam parkinsonism-dementia complex, FTDP-17, Lytico-Bodig disease, multiple sclerosis, and traumatic brain injury (TBI), and combinations thereof. In some embodiments, the condition is a symptom associated with Alzheimer's disease (AD), Parkinson's disease, Huntington’s disease, vascular disease dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, tangle-predominant senile dementia, Pick's disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam parkinsonismdementia complex, FTDP-17, Lytico-Bodig disease, multiple sclerosis, or traumatic brain injury (TBI), or combinations thereof. In some embodiments, the condition is Alzheimer's disease or a symptom associated with Alzheimer’s disease. In some embodiments, the condition is Parkinson's disease or a symptom associated with Parkinson's disease. In some embodiments, the condition is amyotrophic lateral sclerosis or a symptom associated with amyotrophic lateral sclerosis.

[0100] AD involves the accumulation of abnormal neuritic plaques and neurofibrillary tangles in the brain. The most common theory surrounding the etiology of AD is the amyloid hypothesis: failure of amyloid beta (AP) clearance mechanisms contributes to rising A 42 levels in the brain, leading to the oligomerization of Ap42 and deposition as diffuse plaques. Microglial and astrocyte action leads to progressive synaptic and neuritic injury, ionic imbalances and altered kinase and phosphatase activities, causing the formation of tangles. Afterwards, widespread neuronal / nitric dysfunction and cell death occurs. While the amyloid hypothesis remains the prevailing theory, therapeutics targeted immunoclearing of amyloid plaques do not improve cognition, some humans have abundant A deposits without dementia symptoms, and AP accumulation correlates less well with worsening cognition than other biomarkers. Consequently, the biological mechanisms truly driving AD pathology have yet to be elucidated and the existing treatment landscape remains devoid of meaningful therapies.

[0101] Increasing evidence exists suggesting that the calcineurin-NFAT (nuclear factor of activated T-cells) pathway is implicated in AD and dementia. The calcineurin-NFAT pathway is a calcium-dependent signaling cascade that plays a role in regulating gene expression. Increasing intracellular calcium levels leads to the binding of Ca2+with calmodulin, a calcium sensing protein. The Ca2+-calmodulin complex activates the Ca2+ / calmodulin-dependent serine / threonine phosphatase calcineurin, which dephosphorylates NFAT proteins. This allows for NFAT to translocate to the nucleus, functioning as a transcription factor, regulating the immune response, inflammation, synaptic plasticity, and apoptosis.

[0102] Initially, elevated Ca2+levels were found to trigger signaling cascades important to AD pathology. It was later discovered that disrupted calcium homeostasis is a key driver of AP aggregation and tau phosphorylation, and that increased calcium also causes calcineurin hyperactivation. Calcineurin has been found to be upregulated and overactivated in AD, activating reactive / inflammatory processes in astrocytes which trigger astrogliosis and neural injury (Pleiss MM et al., Biochim Biophys Acta. 2016 Sep; 1862(9): 1521-32). It has been confirmed that alterations in calcineurin-NFAT signaling emerge with mild cognitive impairment and are related to dementia progression. Furthermore, CNI administration has demonstrated the potential to block the neurotoxic effects of tau oligomers (Scaduto P, et al., Brain Commun. 2024 Aug 16;6(5). Additionally, calcineurin inhibition can rescue early synaptic plasticity deficits in a mouse model of AD (Cavallucci V, et al., Neuromolecular Med. 2013 Sep: 15(3):541 -8). Most compellingly, a large population of organ transplant patients on CNIs (cyclosporine A and tacrolimus) demonstrated markedly lower rates of AD and dementia than the general population. Cyclosporine A (CsA) lead to reduced dementia prevalence relative to tacrolimus (FK506) (Silva JD, et al., JAlzheimers Dis. 2023;95(2):585-597). While evidence suggests that CNTs may be an effective treatment for neurodegeneration, CNIs can cause a range of toxicities complicating their chronic usage. Consequently, while CNIs may be promising for preventing AD and dementia, finding nontoxic alternatives can best optimize patient outcomes.Therapeutic Effect

[0103] In some embodiments, administering the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof. In some embodiments, the therapeutic effect is achieved by stabilizing or slowing the rate of decline of symptoms during the course of treatment and / or improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof. In some embodiments, the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof.

[0104] In some embodiments, the therapeutic effect is achieved by stabilizing or slowing the accumulation of and / or reducing amyloid-beta plaque levels, tau protein levels, neurofilament light chain levels, or combinations thereof. In some embodiments, the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

[0105] In some embodiments, the therapeutic effect is determined by measuring CSF and / or plasma biomarkers. In some embodiments, the CSF and / or plasma biomarkers are selected from calcineurin-NAFT pathway markers (e.g., NFAT1, pNFAT, IL-2, IL-4, IL-6, YKL-40, TNFa, IFNP, and combinations thereof), amyloid-beta markers (e.g., A04O / 42, sAPPa, sAPPp, CREB / pCREB, and combinations thereof), tau markers (e.g., p-taul81, p-tau217, MTBR-tau-243, and combinations thereof), markers of synaptic dysfunction (e.g., PSD-95, synaptophysin, MMP9, and combinations thereof), markers of neuroinflammation (e.g., GFAP, Iba-1, NfL, and combinations thereof), cytokines and inflammatory markers (e.g., IL-5, IL-8, IL-13, IL-15, CRP, MCP-1, ICAM-1, VCAM-1, and combinations thereof), markers of autophagy (e.g., TFEB, PINK1, BNIP3L, and combinations thereof), markers of ER stress and unfolded protein response (e.g., GRP78, XBP-1, GADD153 / CHOP, SOD1, and combinations thereof), and CFTR markers (e.g., CFTR, NLR2, Caspase-1, IL-1 P, and combinations thereof), and combinations thereof. In some embodiments, the therapeutic effect is determined by cognitive and / or psychiatric assessments. In some embodiments, the cognitive and / or psychiatric assessment is selected fromMini-Mental State Examination, Montreal Cognitive Assessment, Hopkins Verbal Learning Test, Digit Symbol Substitution Test, Verbal Fluency, Alzheimer’s Disease Assessment Scale-Cognitive Subscale, Clinical Dementia Rating Sum of Boxes, and Alzheimer’s Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment, Geriatric Depression Scale - Short, and Columbia-Suicide Severity Rating Scale, and any combination thereof. In some embodiments, the therapeutic effect is evidenced by delaying or arresting symptom progression.

[0106] In some embodiments, the therapeutic effect is evidenced by delaying or arresting biomarker movement. In some embodiments, the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the agent, or a pharmaceutically acceptable salt thereof. In some embodiments, the central exposure level of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is higher in the subject when co- administered with the agent, compared to the central exposure level of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the agent.Subjects

[0107] A “subject,” as used herein, can be any animal, and may also be referred to as the patient. Preferably the subject is a mammal, such as a research animal (e.g., a monkey, rabbit, mouse, or rat) or a domesticated farm animal (e.g., cow, goat, horse, pig) or pet (e.g., dog, cat). In some embodiments, the subject is a human.

[0108] In some embodiments, the subject has a neurodegenerative disease, disorder, or condition. In some embodiments, the subject is cognitively asymptomatic. In some embodiments, the subject has a risk factor for developing a neurodegenerative disease, disorder, or condition. In some embodiments, the risk factor is family history, genetic, presence of absence of a biomarker associated with a neurodegenerative disease, disorder, or condition, or the risk factor is the subject’s age. In some embodiments, the risk factor is current or previous participation in high-impact activities, such as soldiers and athletes. In some embodiments, the subject has a family history of a neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic. In some embodiments, the subject has a genetic predisposition to neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitivelyasymptomatic. In some embodiments, the subject has a genetic predisposition to neurodegenerative disease, condition, or disorder. In some embodiments, the subject has a genetic predisposition to neurodegenerative disease, condition, or disorder and is cognitively asymptomatic. In some embodiments, the subject has tested positive for a biomarker indicating presence of or predisposition to a neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic. In some embodiments, the subject has tested positive for a biomarker indicating presence of or predisposition to a neurodegenerative disease, condition, or disorder. In some embodiments, the subject has tested positive for a biomarker indicating presence of or predisposition to a neurodegenerative disease, condition, or disorder, and is cognitively asymptomatic. In some embodiments, the subject is a human subject. In some embodiments, the subject is an adult. In some embodiments, the subject is at least 50 years old, at least 60 years old, at least 70 years old, or at least 80 years old. In some embodiments, the subject is a child.

[0109] In some embodiments, the subject has cognitive impairment. In some embodiments, the subject has mild, moderate, or severe cognitive impairment. In some embodiments, the subject has mild cognitive impairment.

[0110] In some embodiments, the subject is a human subject. In some embodiments, the subject is an adult. In some embodiments, the subject is a child.Pharmaceutical Compositions

[0111] A compound of the disclosure can be administered in a pharmaceutical composition.

[0112] Pharmaceutical compositions that are useful in the methods of the disclosure can be prepared, packaged, or sold in formulations suitable for ophthalmic, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intravenous, intracerebroventricular, intradermal, intramuscular, or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunogenic-based formulations.

[0113] A pharmaceutical composition of the disclosure can be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient, which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0114] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the disclosure will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0115] In addition to the active ingredient, a pharmaceutical composition of the disclosure can further comprise one or more additional pharmaceutically active agents.

[0116] Controlled- or sustained-release formulations of a pharmaceutical composition of the disclosure may be made using conventional technology.

[0117] As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue -penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, intraocular, intravitreal, subcutaneous, intraperitoneal, intramuscular, intradermal, intrastemal injection, intratumoral, intravenous, intracerebroventricular and kidney dialytic infusion techniques.

[0118] Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition.

[0119] Pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or moreother accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit. The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer’s solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or diglycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt.

[0120] Although the description of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as non-human primates, cattle, pigs, horses, sheep, cats, and dogs.Dosing and Dosing Regimens

[0121] The therapeutic compositions and methods described herein can be administered according to a variety of dosing regimens, treatment schedules, and sequencing paradigms.

[0122] A combination according to the disclosure can be administered in a prescribed dosing regimen for a period of, e.g., at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months or longer. In someembodiments, chronic treatment refers to administration of at least about 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or longer.

[0123] In some embodiments, a suitable amount of the compound effective to provide a therapeutic effect ranges from about 1 to about 3,000 mg per day, for example about 10 mg per day, about 20 mg per day, about 30 mg per day, about 40 mg per day, about 50 mg per day, about 60 mg per day, about 70 mg per day, about 80 mg per day, about 90 mg per day, about 100 mg per day, about 120 mg per day, about 140 mg per day, about 160 mg per day, about 180 mg per day, about 200 mg per day, about 220 mg per day, about 240 mg per day, about 260 mg per day, about 280 mg per day, about 300 mg per day, about 320 mg per day, about 340 mg per day, about 360 mg per day, about 380 mg per day, about 400 mg per day, about 420 mg per day, about 440 mg per day, about 460 mg per day, about 480 mg per day, about 500 mg per day, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 1,000 mg per day, about 1,100 mg per day, about 1,200 mg per day, about 1,300 mg per day, about 1,400 mg per day, about 1,500 mg per day, about 1,600 mg per day, about 1,700 mg per day, about 1,800 mg per day, about 1,900 mg per day, or about 2,000 mg per day.

[0124] A compound described herein can be present in a composition in a range of from about 1 mg to about 2000 mg; from about 1 mg to about 1000 mg; from about 1 mg to about 500 mg; from about 5 mg to about 1000 mg, from about 5 mg to about 500 mg, from about 5 mg to about 100 mg, from about 10 mg to about 50 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900 mg, from about 900 mg to about 950 mg, or from about 950 mg to about 1000 mg.

[0125] A compound described herein can be present in a composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, or about 2000 mg.

[0126] In some embodiments, a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drug per kilograms of subject body mass. In some embodiments, a compound is administered in an amount ranging from about 0.01 mg / kg to about 2,000 mg / kg, about 0.01 mg / kg to about 1,000 mg / kg, about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.01 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.5 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, about 0.01 mg / kg to about 0.05 mg / kg, about 1 mg / kg to about 1,000 mg / kg, about 1 mg / kg to about 500 mg / kg, about 1 mg / kg to about 250 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 50 mg / kg, about 5 mg / kg to about 50 mg / kg, about 5 mg / kg to about 10 mg / kg, about 5 mg / kg to about 20 mg / kg, about 10 mg / kg to about 50 mg / kg, about 10 mg / kg to about 20 mg / kg, about 250 mg / kg to about 2000 mg / kg, about 10 mg / kg to about 800 mg / kg, about 50 mg / kg to about 400 mg / kg, about 100 mg / kg to about 300 mg / kg, or about 150 mg / kg to about 200 mg / kg. In some embodiments, a compound is administered in an amount of about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg or about 1,000 mg / kg of subject body mass.

[0127] In some embodiments, a dose can be expressed in terms of an amount of the drug divided by the mass of the subject per day, for example, milligrams of drug per kilograms of subject body mass, per day (mg / kg / day). In some embodiments, a compound is administered in an amount ranging from about 0.01 mg / kg / day to about 2,000 mg / kg / day, about 0.01 mg / kg / day to about 1,000 mg / kg / day, about 0.01 mg / kg / day to about 100 mg / kg / day, about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg to about 5 mg / kg / day, about 0.01 mg / kg / day to about 1 mg / kg / day, about 0.01 mg / kg / day to about 0.5 mg / kg / day, about 0.01 mg / kg / day to about 0.1 mg / kg / day, about 0.01 mg / kg / day to about 0.05 mg / kg / day, about 1 mg / kg / day to about 1,000 mg / kg / day, about 1 mg / kg / day to about 500 mg / kg / day, about 1 mg / kg / day to about 250 mg / kg / day, about 1 mg / kg / day to about 100 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day,about 5 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 10 mg / kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 10 mg / kg / day to about 50 mg / kg / day, about 10 mg / kg / day to about 20 mg / kg / day, about 250 mg / kg / day to about 2000 mg / kg / day, about 10 mg / kg / day to about 800 mg / kg / day, about 50 mg / kg / day to about 400 mg / kg / day, about 100 mg / kg / day to about 300 mg / kg / day, or about 150 mg / kg / day to about 200 mg / kg / day. In some embodiments, a compound is administered in an amount of about 1 mg / kg / day, about 2 mg / kg / day, about 5 mg / kg / day, about 10 mg / kg / day, about 20 mg / kg / day, about 50 mg / kg / day, about 100 mg / kg / day, about 150 mg / kg / day, about 200 mg / kg / day, about 250 mg / kg / day, about 300 mg / kg / day, about 350 mg / kg / day, about 400 mg / kg / day, about 450 mg / kg / day, about 500 mg / kg / day, about 550 mg / kg / day, about 600 mg / kg / day, about 650 mg / kg / day, about 700 mg / kg / day, about 750 mg / kg / day, about 800 mg / kg / day, about 850 mg / kg / day, about 900 mg / kg / day, about 950 mg / kg / day or about 1,000 mg / kg / day of subject body mass per day.Definitions

[0128] All scientific and technical terms used in the present application have meanings commonly used in the art unless otherwise specified. The definitions provided herein are to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present application.

[0129] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pymvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0130] The term “pharmaceutical composition” generally refers to a composition comprising a pharmaceutically active ingredient, in combination with at least one additional pharmaceutically acceptable carrier. A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to an individual, including, e.g., an adjuvant, an excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Suitable carriers include without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. Pharmaceutical compounds are formulated according to several factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable earners include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0131] As used herein, “condition” refers to any state of health that deviates from normal and requires medical attention. For example, a condition may be a formally diagnosed impairment of normal physical or mental function. Conditions include, but are not limited to, diseases and disorders. Conditions may be acute or chronic. In some embodiments, conditions are identified by family history or biomarkers in the absence of symptoms. In some embodiments, conditions are identified by presentation of symptoms.

[0132] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but, in certain instances, not limited to a therapeutic benefit. Therapeutic effect refers to eradication oramelioration of the underlying disorder being treated. A therapeutic effect is also achieved with the reduction, eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the individual, notwithstanding that the individual may still be afflicted with the underlying disorder. A therapeutic effect is also achieved by delaying, slowing or halting progression of an underlying disorder or a symptom of an underlying disorder compared to a control individual not receiving treatment.

[0133] A “therapeutic effect," as that term is used herein, encompasses a therapeutic benefit. A “prophylactic effect” includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In certain embodiments, for prophylactic benefit, the compositions are administered to an individual at risk of developing a particular disease, or to an individual reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made, or an individual who is asymptomatic to a particular condition, but has tested positive for a biomarker associated with the condition.

[0134] As used herein, the term “effective amount” in connection with a compound means an amount capable of treating, preventing, or managing a disorder, disease, or condition, or one or more symptoms thereof.

[0135] As used herein, the term “preventing” or “prevent” refers to an approach for preventing a disorder, disease, or condition, or one or more symptoms thereof, or reducing the ultimate severity of the disorder, disease, or condition, or of one or more symptoms thereof, or delaying the onset of a disease, disorder, or condition, or one or more symptoms thereof.

[0136] As used herein, the term “synergistic effect” refers to a combined effect of multiple components that is greater than the sum of their individual effects.

[0137] As used herein, the term “additive effect” refers to a combined effect of multiple components that is the sum of their individual effects.

[0138] “Subject” refers to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the individual is a mammal, and in some embodiments, the individual is human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. In some embodiments, the human is > 18 years of age. Insome embodiments, the human is less than 18 years of age, less than 12 years of age, less than 6, 5, 4, 3, 2, or 1 year of age.

[0139] The term “co-administration,” “administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including a human, simultaneously in separate compositions, administration at different times in separate compositions (e.g., during the same treatment cycle, on the same and / or different days), or administration in a composition in which both agents are present.

[0140] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0141] The term “agonist” as used herein refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inducing the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target protein. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that induce or enhance a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0142] “Signal transduction” is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response. A modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway. A modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.

[0143] As used herein, a “sample” includes and / or refers to any fluid or liquid sample which is being analyzed in order to detect and / or quantify an analyte. In some embodiments, a sample is a biological sample. Examples of samples include without limitation a bodily fluid, an extract, a solution containing proteins and / or DNA, a cell extract, a cell lysate, or a tissue lysate. Non-limiting examples of bodily fluids include urine, saliva, blood, serum, plasma, cerebrospinal fluid, tears, semen, sweat, pleural effusion, liquified fecal matter, and lacrimal gland secretion.

[0144] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which theseexemplary embodiments belong. The terminology used in the description herein is for describing particular exemplary embodiments only and is not intended to be limiting of the exemplary embodiments. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0145] As used herein, the words “comprising” (and any form of comprising, such as “comprise" and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps. As also used herein, in any instance or embodiment described herein, “comprising” may be replaced with “consisting essentially of’ and / or “consisting of.” As used herein, in any instance or embodiment described herein, “comprises” may be replaced with “consists essentially of’ and / or “consists of.”

[0146] As used herein, the term “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example, “A and / or B” is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each were set out individually herein.

[0147] As used herein, the term “about,” when used in connection with doses, amounts, or weight percentages, mean a dose, amount, or weight percent within 10%, or within 5%, or within 2%, or within 1% of the stated amount.

[0148] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Where a numerical value is used herein, such a value may encompass a range that is ± 5% of the stated numerical value.

[0149] Specific, non-limiting, and illustrative aspects and embodiments of the subject matter described herein are provided below as numbered embodiments.

[0150] Embodiment 1 : A method of treating a condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) an agent, or a pharmaceutically acceptable salt thereof, that is(a) a CYP3A4 inducer; and / or(b) a P-glycoprotein (P-gp) inhibitor.

[0151] Embodiment 2: The method of embodiment 1, wherein the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the agent, or the pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

[0152] Embodiment 3: The method of embodiment 2, wherein the therapeutic effect is synergistic.

[0153] Embodiment 4: The method of embodiment 2, wherein the therapeutic effect is additive.

[0154] Embodiment 5: The method of embodiment 1, wherein the agent is a CYP3A4 inducer and a P-glycoprotein (P-gp) inhibitor.

[0155] Embodiment 6: The method of any one of embodiments 1 to 5, wherein the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0156] Embodiment 7: The method of any one of embodiments 1 to 6, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

[0157] Embodiment 8: The method of any one of embodiments 1 to 7, wherein the agent is lumacaftor, or a pharmaceutically acceptable salt thereof.

[0158] Embodiment 9: The method of any one of embodiments 1 to 7, wherein the agent, or the pharmaceutically acceptable salt thereof is selected from a compound of Schedule A.

[0159] Embodiment 10: The method of any one of embodiments 1 to 9, wherein the CYP3A4 inducer increases CYP3A4 activity and / or increases CYP3A4 expression.

[0160] Embodiment 11 : The method of any one of embodiments 1 to 10, wherein the P-gp inhibitor inhibits P-gp activity and / or decreases P-gp expression.

[0161] Embodiment 12: The method of any one of embodiments 1 to 11, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are each administered orally.

[0162] Embodiment 13: The method of any one of embodiments 1 to 11, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the agent (e.g., lumacaftor) is administered orally.

[0163] Embodiment 14: The method of any one of embodiments 1 to 11, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered orally and the agent (e.g., lumacaftor) is administered intravenously.

[0164] Embodiment 15: The method of any one of embodiments 1 to 11, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are each administered intravenously.

[0165] Embodiment 16: The method of any one of embodiments 1 to 15, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are sequentially administered.

[0166] Embodiment 17: The method of any one of embodiments 1 to 15, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g., lumacaftor) are concurrently administered.

[0167] Embodiment 18: The method of any one of embodiments 1 to 17, wherein the calcineurin inhibitor is administered once, twice, or three times a day.

[0168] Embodiment 19: The method of any one of embodiments 1 to 18, wherein the agent is administered once, twice, or three times a day.

[0169] Embodiment 20: The method of any one of embodiments 1 to 19, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 0.075mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses.

[0170] Embodiment 21: The method of any one of embodiments 1 to 19, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg to about 25 mg administered in one or two daily doses.

[0171] Embodiment 22: The method of any one of embodiments 1 to 19, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses.

[0172] Embodiment 23: The method of any one of embodiments 1 to 22, wherein the agent is lumacaftor, and the therapeutically effective amount is a dose of about 100 mg / day to about 800 mg / day administered in one or two daily doses.

[0173] Embodiment 24: The method of any one of embodiments 20 to 23, wherein the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0174] Embodiment 25: The method of embodiment 24,wherein the therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.15 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

[0175] Embodiment 26: The method of any one of embodiments 1 to 8, or 10 to 25, wherein lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times higher than the second daily dose.

[0176] Embodiment 27: The method of any one of embodiments 1 to 26, wherein the administering results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

[0177] Embodiment 28: The method of embodiment 27, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0178] Embodiment 29: The method of embodiment 27 or 28, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0179] Embodiment 30: The method of embodiment 27 or 28, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0180] Embodiment 31 : The method of any one of embodiments 1 to 30, wherein the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

[0181] Embodiment 32: The method of embodiment 31, wherein the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof.

[0182] Embodiment 33: The method of embodiment 31, wherein the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, a decrease in neurofilament light chain levels, or combinations thereof.

[0183] Embodiment 34: The method of embodiment 31, wherein the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

[0184] Embodiment 35: The method of any one of embodiments 31 to 34, wherein the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0185] Embodiment 36: The method of any one of embodiments 1 to 35, wherein the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the agent.

[0186] Embodiment 37: The method of any one of embodiments 1 to 36, wherein the administering results in increased central nervous system concentration of the calcineurin inhibitor.

[0187] Embodiment 38: The method of embodiment 37, wherein the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

[0188] Embodiment 39: The method of embodiment 38, wherein the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0189] Embodiment 40: The method of any one of embodiments 1 to 39, wherein the administering results in decreased peripheral concentration (e.g., plasma, blood or tissueconcentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent.

[0190] Embodiment 41 : The method of embodiment 40, wherein decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject.

[0191] Embodiment 42: The method of embodiment 41, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0192] Embodiment 43: The method of embodiment 41 or 42, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0193] Embodiment 44: The method of embodiment 41 or 42, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0194] Embodiment 45: The method of any one of embodiments 1 to 44, wherein the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0195] Embodiment 46: A method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising:(i) tacrolimus, or a pharmaceutically acceptable salt thereof; and(ii) lumacaftor, or a pharmaceutically acceptable salt thereof.

[0196] Embodiment 47: The method of embodiment 46, wherein tacrolimus, or the pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

[0197] Embodiment 48: The method of embodiment 47, wherein the therapeutic effect is synergistic.

[0198] Embodiment 49: The method of embodiment 47, wherein the therapeutic effect is additive.

[0199] Embodiment 50: The method of any one of embodiments 46 to 49, wherein tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are each administered orally.

[0200] Embodiment 51: The method of any one of embodiments 46 to 49, wherein tacrolimus, or a pharmaceutically acceptable salt thereof, is administered intravenously and lumacaftor, or a pharmaceutically acceptable salt thereof, is administered orally.

[0201] Embodiment 52: The method of any one of embodiments 46 to 49, wherein tacrolimus, or a pharmaceutically acceptable salt thereof, is administered orally and lumacaftor, or a pharmaceutically acceptable salt thereof, is administered intravenously.

[0202] Embodiment 53: The method of any one of embodiments 46 to 49, wherein tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are each administered intravenously.

[0203] Embodiment 54: The method of any one of embodiments 46 to 53, wherein tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are sequentially administered.

[0204] Embodiment 55: The method of any one of embodiments 46 to 53, wherein tacrolimus, or a pharmaceutically acceptable salt thereof, and lumacaftor, or a pharmaceutically acceptable salt thereof, are concurrently administered.

[0205] Embodiment 56: The method of any one of embodiments 46 to 55, wherein tacrolimus, or a pharmaceutically acceptable salt thereof, is administered once, twice, or three times a day.

[0206] Embodiment 57: The method of any one of embodiments 46 to 56, wherein lumacaftor, or a pharmaceutically acceptable salt thereof, is administered once, twice, or three times a day.

[0207] Embodiment 58: The method of any one of embodiments 46 to 57, wherein the therapeutically effective amount of tacrolimus is about 0.075mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses.

[0208] Embodiment 59: The method of any one of embodiments 46 to 57, wherein the therapeutically effective amount of tacrolimus is about 3 mg to about 25 mg administered in one or two daily doses.

[0209] Embodiment 60: The method of any one of embodiments 46 to 57, the therapeutically effective amount of tacrolimus is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses.

[0210] Embodiment 61 : The method of any one of embodiments 46 to 58, wherein the therapeutically effective amount of lumacaftor is about 100 mg / day to about 800 mg / day administered in one or two daily doses.

[0211] Embodiment 62: The method of any one of embodiments 58 to 60, wherein the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0212] Embodiment 63 : The method of embodiment 62,wherein the therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.15 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

[0213] Embodiment 64: The method of any one of embodiments 46 to 63, wherein lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times greater than the second daily dose.

[0214] Embodiment 65: The method of any one of embodiments 46 to 63, wherein the administering results in reduced systemic toxicity of tacrolimus or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered tacrolimus or the pharmaceutically acceptable salt thereof in absence of lumacaftor or the pharmaceutically acceptable salt thereof.

[0215] Embodiment 66: The method of embodiment 65, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0216] Embodiment 67: The method of embodiment 65 or 66, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0217] Embodiment 68: The method of embodiment 65 or 66, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0218] Embodiment 69: The method of any one of embodiments 46 to 68, wherein the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered tacrolimus or the pharmaceutically acceptable salt thereof in absence of lumacaftor or the pharmaceutically acceptable salt thereof.

[0219] Embodiment 70: The method of embodiment 69, wherein the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof.

[0220] Embodiment 71: The method of embodiment 69, wherein the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof.

[0221] Embodiment 72: The method of embodiment 69, wherein the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

[0222] Embodiment 73: The method of any one of embodiments 69 to 72, wherein the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0223] Embodiment 74: The method of any one of embodiments 46 to 73, wherein the therapeutically-effective amount of tacrolimus, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of tacrolimus, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of lumacaftor, or the pharmaceutically acceptable salt thereof.

[0224] Embodiment 75: The method of any one of embodiments 46 to 74, wherein the administering increases central nervous system concentration of tacrolimus, or the pharmaceutically acceptable salt thereof.

[0225] Embodiment 76: The method of embodiment 75, wherein the central nervous system concentration of tacrolimus, or the pharmaceutically acceptable salt thereof, is higher compared to a control subject administered tacrolimus, or the pharmaceutically acceptable salt thereof, in absence of lumacaftor, or the pharmaceutically acceptable salt thereof.

[0226] Embodiment 77 : The method of embodiment 75 or 76, wherein the central nervous system concentration of tacrolimus, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0227] Embodiment 78: The method of any one of embodiments 46 to 77, wherein the administering results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of tacrolimus or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered tacrolimus or the pharmaceutically acceptable salt thereof, in absence of lumacaftor or of the pharmaceutically acceptable salt thereof.

[0228] Embodiment 79: The method of embodiment 78, wherein decreasing the peripheral concentration of tacrolimus, or the pharmaceutically acceptable salt thereof, in the subject reduces systemic toxicity in the subject.

[0229] Embodiment 80: The method of embodiment 79, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0230] Embodiment 81: The method of embodiment 79 or 80, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0231] Embodiment 82: The method of embodiment 79 or 80, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0232] Embodiment 83: The method of any one of embodiments 46 to 82, wherein the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of tacrolimus, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0233] Embodiment 84: A method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) an agent, or a pharmaceutically acceptable salt thereof, that exhibits calcineurin inhibitor-like properties.

[0234] Embodiment 85: The method of embodiment 84, wherein the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the agent, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

[0235] Embodiment 86: The method of embodiment 85, wherein the therapeutic effect is synergistic.

[0236] Embodiment 87: The method of embodiment 85, wherein the therapeutic effect is additive.

[0237] Embodiment 88: The method of any one of embodiments 84 to 87, wherein the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0238] Embodiment 89: The method of any one of embodiments 84 to 87, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

[0239] Embodiment 90: The method of any one of embodiments 84 to 89, wherein the agent is lumacaftor, or a pharmaceutically acceptable salt thereof.

[0240] Embodiment 91: The method of any one of embodiments 84 to 90, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are each administered orally.

[0241] Embodiment 92: The method of any one of embodiments 84 to 90, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the agent (e.g. lumacaftor) is administered orally.

[0242] Embodiment 93: The method of any one of embodiments 84 to 90, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered orally and the agent (e.g. lumacaftor) is administered intravenously.

[0243] Embodiment 94: The method of any one of embodiments 84 to 90, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are each administered intravenously.

[0244] Embodiment 95: The method of any one of embodiments 84 to 94, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are sequentially administered.

[0245] Embodiment 96: The method of any one of embodiments 84 to 94, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are concurrently administered.

[0246] Embodiment 97 : The method of any one of embodiments 84 to 96, wherein the calcineurin inhibitor is administered once, twice, or three times a day.

[0247] Embodiment 98: The method of any one of embodiments 84 to 97, wherein the agent is administered once, twice, or three times a day.

[0248] Embodiment 99: The method of any one of embodiments 84 to 98, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 0.075mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses.

[0249] Embodiment 100: The method of any one of embodiments 84 to 98, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg to about 25 mg administered in one or two daily doses.

[0250] Embodiment 101: The method of any one of embodiments 84 to 98, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses.

[0251] Embodiment 102: The method of any one of embodiments 84 to 101, wherein the agent is lumacaftor, and the therapeutically effective amount is a dose of about 100 mg / day to about 800 mg / day administered in one or two daily doses.

[0252] Embodiment 103: The method of any one of embodiments 99 to 102, wherein the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0253] Embodiment 104: The method of embodiment 103, wherein the therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor: orwherein the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.15 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

[0254] Embodiment 105: The method of any one of embodiments 102 to 104, wherein lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times greater than the second daily dose.

[0255] Embodiment 106: The method of any one of embodiments 84 to 105, wherein the administering results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0256] Embodiment 107: The method of embodiment 106, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0257] Embodiment 108: The method of embodiment 106 or 107, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0258] Embodiment 109: The method of embodiment 106 or 107, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0259] Embodiment 110: The method of any one of embodiments 84 to 109, wherein the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0260] Embodiment 111: The method of embodiment 110, wherein the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof.

[0261] Embodiment 112: The method of embodiment 110, wherein the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof.

[0262] Embodiment 113: The method of embodiment 110, wherein the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

[0263] Embodiment 114: The method of any one of embodiments 110 to 113, wherein the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0264] Embodiment 115: The method of any one of embodiments 84 to 114, wherein the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0265] Embodiment 116: The method of any one of embodiments 84 to 115, wherein the administering results in increased central nervous system concentration of the calcineurin inhibitor.

[0266] Embodiment 117: The method of embodiment 116, wherein the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0267] Embodiment 118: The method of embodiment 116, wherein the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0268] Embodiment 119: The method of any one of embodiments 84 to 118, wherein the administering results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0269] Embodiment 120: The method of embodiment 119, wherein decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject.

[0270] Embodiment 121: The method of embodiment 120, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0271] Embodiment 122: The method of embodiment 120 or 121, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0272] Embodiment 123: The method of embodiment 120 or 121, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0273] Embodiment 124: The method of any one of embodiments 84 to 123, wherein the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0274] Embodiment 125: A method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound, or a pharmaceutically acceptable salt thereof.

[0275] Embodiment 126: The method of embodiment 125, wherein the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the CFTR modulating compound, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

[0276] Embodiment 127 : The method of embodiment 126, wherein the therapeutic effect is synergistic.

[0277] Embodiment 128: The method of embodiment 126, wherein the therapeutic effect is additive.

[0278] Embodiment 129: The method of any one of embodiments 125 to 128, wherein the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0279] Embodiment 130: The method of any one of embodiments 125 to 128, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 131: The method of any one of embodiments 125 to 130, wherein the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, is a CFTR potentiator, corrector, dual-acting potentiator and corrector, or a combination thereof.

[0281] Embodiment 132: The method of any one of embodiments 125 to 130, wherein the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, is a CFTR corrector.

[0282] Embodiment 1 3: The method of any one of embodiments 125 to 130, wherein the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, comprises calcineurin inhibitor-like activity.

[0283] Embodiment 134: The method of any one of embodiments 125 to 130, wherein the CFTR modulating compound is a compound from Schedule B.

[0284] Embodiment 135: The method of any one of embodiments 125 to 130, wherein the CFTR modulating compound is lumacaftor, vanzacaftor, tezacaftor, deutivacaftor, elexacaftor, or ivacaftor, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0285] Embodiment 136: The method of any one of embodiments 125 to 130, wherein the CFTR modulating compound is lumacaftor, or the pharmaceutically acceptable salt thereof.

[0286] Embodiment 137: The method of any one of embodiments 125 to 136, wherein the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g. lumacaftor) are each administered orally.

[0287] Embodiment 138: The method of any one of embodiments 125 to 136, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the CFTR modulating compound (e.g. lumacaftor) is administered orally.

[0288] Embodiment 139: The method of any one of embodiments 125 to 136, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered orally and the CFTR modulating compound is administered intravenously.

[0289] Embodiment 140: The method of any one of embodiments 125 to 136, wherein the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g. lumacaftor) are each administered intravenously.

[0290] Embodiment 141 : The method of any one of embodiments 125 to 140, wherein the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g. lumacaftor) are sequentially administered.

[0291] Embodiment 142: The method of any one of embodiments 125 to 140, wherein the calcineurin inhibitor (e.g., tacrolimus) and the CFTR modulating compound (e.g. lumacaftor) are concurrently administered.

[0292] Embodiment 143: The method of any one of embodiments 125 to 142, wherein the calcineurin inhibitor is administered once, twice, or three times a day.

[0293] Embodiment 144: The method of any one of embodiments 125 to 143, wherein the CFTR modulating compound is administered once, twice, or three times a day.

[0294] Embodiment 145: The method of any one of embodiments 125 to 144, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 0.075mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses.

[0295] Embodiment 146: The method of any one of embodiments 125 to 144, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg to about 25 mg administered in one or two daily doses.

[0296] Embodiment 147: The method of any one of embodiments 125 to 144, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses.

[0297] Embodiment 148: The method of any one of embodiments 125 to 147, wherein the CFTR modulating compound is lumacaftor, and the therapeutically effective amount is a dose of about 100 mg / day to about 800 mg / day administered in one or two daily doses.

[0298] Embodiment 149: The method of any one of embodiments 145 to 148, wherein the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0299] Embodiment 150: The method of embodiment 149,wherein the therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.15 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

[0300] Embodiment 151: The method of any one of embodiments 148 to 150, wherein lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times greater than the second daily dose.

[0301] Embodiment 152: The method of any one of embodiments 125 to 151, wherein the administering results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the CFTR modulating compound.

[0302] Embodiment 153: The method of embodiment 152, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0303] Embodiment 154: The method of embodiment 152 or 153, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0304] Embodiment 155: The method of embodiment 152 or 153, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0305] Embodiment 156: The method of any one of embodiments 125 to 155, wherein the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the CFTR modulating compound.

[0306] Embodiment 157: The method of embodiment 156, wherein the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof.

[0307] Embodiment 158: The method of embodiment 156, wherein the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof.

[0308] Embodiment 159: The method of embodiment 156, wherein the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

[0309] Embodiment 160: The method of any one of embodiments 156 to 159, wherein the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0310] Embodiment 161: The method of any one of embodiments 125 to 160, wherein the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptablesalt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the CFTR modulating compound.

[0311] Embodiment 162: The method of any one of embodiments 125 to 161, wherein the administering results in increased central nervous system concentration of the calcineurin inhibitor.

[0312] Embodiment 163: The method of embodiment 162, wherein the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the CFTR modulating compound.

[0313] Embodiment 164: The method of embodiment 162 or 163, wherein the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0314] Embodiment 165: The method of any one of embodiments 125 to 164, wherein the administering results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the CFTR modulating compound.

[0315] Embodiment 166: The method of embodiment 165, wherein decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject,

[0316] Embodiment 167 : The method of embodiment 166, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0317] Embodiment 168: The method of embodiment 166 or 167, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0318] Embodiment 169: The method of embodiment 166 or 167, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0319] Embodiment 170: The method of any one of embodiments 125 to 169, wherein the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0320] Embodiment 171: A method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) an agent from Schedule A or Schedule B, or a pharmaceutically acceptable salt thereof.

[0321] Embodiment 172: The method of embodiment 171, wherein the calcineurin inhibitor or the pharmaceutically acceptable salt thereof, and the agent or the pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

[0322] Embodiment 173: The method of embodiment 172, wherein the therapeutic effect is synergistic.

[0323] Embodiment 174: The method of embodiment 172, wherein the therapeutic effect is additive.

[0324] Embodiment 175: The method of any one of embodiments 171 to 174, wherein the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof.

[0325] Embodiment 176: The method of any one of embodiments 171 to 175, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

[0326] Embodiment 177: The method of any one of embodiments 171 to 175, wherein the agent is lumacaftor, or a pharmaceutically acceptable salt thereof.

[0327] Embodiment 178: The method of any one of embodiments 171 to 177, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are each administered orally.

[0328] Embodiment 179: The method of any one of embodiments 171 to 177, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are administered orally.

[0329] Embodiment 180: The method of any one of embodiments 171 to 177, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are administered intravenously.

[0330] Embodiment 181 : The method of any one of embodiments 171 to 177, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are each administered intravenously.

[0331] Embodiment 182: The method of any one of embodiments 171 to 181, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are sequentially administered.

[0332] Embodiment 183: The method of any one of embodiments 171 to 181, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are concurrently administered.

[0333] Embodiment 184: The method of any one of embodiments 171 to 183, wherein the calcineurin inhibitor is administered once, twice, or three times a day.

[0334] Embodiment 185: The method of any one of embodiments 171 to 184, wherein the agent is administered once, twice, or three times a day.

[0335] Embodiment 186: The method of any one of embodiments 171 to 185, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 0.075mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses.

[0336] Embodiment 187: The method of any one of embodiments 171 to 185, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg to about 25 mg administered in one or two daily doses.

[0337] Embodiment 188: The method of any one of embodiments 171 to 185, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses.

[0338] Embodiment 189: The method of any one of embodiments 171 to 188, wherein the agent is lumacaftor, and the therapeutically effective amount is a dose of about 100 mg / day to about 800 mg / day administered in one or two daily doses.

[0339] Embodiment 190: The method of any one of embodiments 186 to 189, wherein the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0340] Embodiment 191: The method of embodiment 190,wherein the therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

[0341] Embodiment 192: The method of any one of embodiments 189 to 191, wherein lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times greater than the second daily dose.

[0342] Embodiment 193: The method of any one of embodiments 171 to 192, wherein the administering results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

[0343] Embodiment 194: The method of embodiment 193, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0344] Embodiment 195: The method of embodiment 193 or 194, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0345] Embodiment 196: The method of embodiment 193 or 194, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0346] Embodiment 197: The method of any one of embodiments 171 to 196, wherein the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

[0347] Embodiment 198: The method of embodiment 197, wherein the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof.

[0348] Embodiment 199: The method of embodiment 197, wherein the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof.

[0349] Embodiment 200: The method of embodiment 197, wherein the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

[0350] Embodiment 201: The method of any one of embodiments 197 to 200, wherein the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0351] Embodiment 202: The method of any one of embodiments 171 to 201, wherein the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the agent.

[0352] Embodiment 203: The method of any one of embodiments 171 to 202, wherein the administering results in increased central nervous system concentration of the calcineurin inhibitor.

[0353] Embodiment 204: The method of embodiment 203, wherein the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

[0354] Embodiment 205: The method of embodiment 204, wherein the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0355] Embodiment 206: The method of any one of embodiments 171 to 205, wherein the administering results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent.

[0356] Embodiment 207: The method of embodiment 206, wherein decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject.

[0357] Embodiment 208: The method of embodiment 207, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0358] Embodiment 209: The method of embodiment 207 or 208, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0359] Embodiment 210: The method of embodiment 207 or 208, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0360] Embodiment 211: The method of any one of embodiments 171 to 210, wherein the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0361] Embodiment 212: A method of treating a condition, comprising administering to a subject a therapeutically-effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) an agent, or a pharmaceutically acceptable salt thereof, that(a) increases a therapeutic effect;(b) reduces systemic toxicity;(c) increases central nervous system concentration; and / or(d) reduces a therapeutically-effective dose;of the calcineurin inhibitor or a pharmaceutically acceptable salt thereof.

[0362] Embodiment 213: The method of embodiment 212, wherein the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the agent, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

[0363] Embodiment 214: The method of embodiment 213, wherein the therapeutic effect is synergistic.

[0364] Embodiment 215: The method of embodiment 213, wherein the therapeutic effect is additive.

[0365] Embodiment 216: The method of any one of embodiments 212 to 215, wherein the calcineurin inhibitor is tacrolimus (EK506) or a derivative thereof, cyclosporin (CsA),voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0366] Embodiment 217: The method of any one of embodiments 212 to 215, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

[0367] Embodiment 218: The method of any one of embodiments 212 to 217, wherein the agent, or the pharmaceutically acceptable salt thereof, is a compound from Schedule A or Schedule B.

[0368] Embodiment 219: The method of any one of embodiments 212 to 217, wherein the agent is lumacaftor, or a pharmaceutically acceptable salt thereof.

[0369] Embodiment 220: The method of any one of embodiments 212 to 219, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are each administered orally.

[0370] Embodiment 221 : The method of any one of embodiments 212 to 219, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered intravenously and the agent (e.g. lumacaftor) is administered orally.

[0371] Embodiment 222: The method of any one of embodiments 212 to 219, wherein the calcineurin inhibitor (e.g., tacrolimus) is administered orally and the agent (e.g. lumacaftor) is administered intravenously.

[0372] Embodiment 223: The method of any one of embodiments 212 to 219, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are each administered intravenously.

[0373] Embodiment 224: The method of any one of embodiments 212 to 223, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are sequentially administered.

[0374] Embodiment 225: The method of any one of embodiments 212 to 223, wherein the calcineurin inhibitor (e.g., tacrolimus) and the agent (e.g. lumacaftor) are concurrently administered.

[0375] Embodiment 226: The method of any one of embodiments 212 to 225, wherein the calcineurin inhibitor is administered once, twice, or three times a day.

[0376] Embodiment 227: The method of any one of embodiments 212 to 226, wherein the agent is administered once, twice, or three times a day.

[0377] Embodiment 228: The method of any one of embodiments 212 to 227, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 0.075mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses.

[0378] Embodiment 229: The method of any one of embodiments 212 to 227, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg to about 25 mg administered in one or two daily doses.

[0379] Embodiment 230: The method of any one of embodiments 212 to 227, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses.

[0380] Embodiment 231 : The method of any one of embodiments 212 to 230, wherein the agent is lumacaftor, and the therapeutically effective amount is a dose of about 100 mg / day to about 800 mg / day administered in one or two daily doses.

[0381] Embodiment 232: The method of any one of embodiments 228 to 231, wherein the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

[0382] Embodiment 233: The method of embodiment 232, whereinthe therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.15 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

[0383] Embodiment 234: The method of any one of embodiments 231 to 233, wherein lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times greater than the second daily dose.

[0384] Embodiment 235: The method of any one of embodiments 212 to 234, wherein the administering results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subjectadministered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0385] Embodiment 236: The method of embodiment 235, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0386] Embodiment 237: The method of embodiment 235 or 236, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0387] Embodiment 238: The method of embodiment 235 or 236, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1, or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0388] Embodiment 239: The method of any one of embodiments 212 to 238, wherein the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or a pharmaceutically acceptable salt thereof.

[0389] Embodiment 240: The method of embodiment 239, wherein the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof.

[0390] Embodiment 241: The method of embodiment 239, wherein the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, or decrease in neurofilament light chain levels, or combinations thereof.

[0391] Embodiment 242: The method of embodiment 239, wherein the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

[0392] Embodiment 243: The method of any one of embodiments 239 to 242, wherein the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0393] Embodiment 244: The method of any one of embodiments 212 to 243, wherein the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the agent, or a pharmaceutically acceptable salt thereof.

[0394] Embodiment 245: The method of any one of embodiments 212 to 244, wherein the administering results in increased central nervous system concentration of the calcineurin inhibitor.

[0395] Embodiment 246: The method of embodiment 245, wherein the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0396] Embodiment 247: The method of embodiment 245 or 246, wherein the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0397] Embodiment 248: The method of any one of embodiments 212 to 247, wherein the administering results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent, or the pharmaceutically acceptable salt thereof.

[0398] Embodiment 249: The method of embodiment 248, wherein decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject.

[0399] Embodiment 250: The method of embodiment 249, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

[0400] Embodiment 251: The method of embodiment 249 or 250, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0401] Embodiment 252: The method of embodiment 249 or 250, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

[0402] Embodiment 253: The method of any one of embodiments 212 to 252, wherein the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) ofthe calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0403] Embodiment 254: The method of any one of embodiments 1 to 253, wherein treating the condition comprises delaying or arresting symptom progression (e.g., cognitive decline).

[0404] Embodiment 255: The method of any one of embodiments 1 to 253, wherein treating the condition comprises delaying or arresting biomarker movement.

[0405] Embodiment 256: A method of reducing systemic toxicity in a subject who is being treated with tacrolimus, or a pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0406] Embodiment 257: A method of decreasing a therapeutically-effective amount of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject who is receiving tacrolimus or the pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0407] Embodiment 258: A method of increasing central nervous system concentration of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0408] Embodiment 259: A method of decreasing peripheral concentration of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

[0409] Embodiment 260: The method of any one of embodiments 1 to 259, wherein the subject is cognitively asymptomatic.

[0410] Embodiment 261: The method of any one of embodiments 1 to 260, wherein the subject has a risk factor for developing a neurodegenerative disease, disorder, or condition.

[0411] Embodiment 262: The method of embodiment 261, wherein the risk factor is family history, genetic, presence of absence of a biomarker associated with a neurodegenerative disease, disorder, or condition, the subject’s age, or the subject’s current or previous participation in high-impact activities.

[0412] Embodiment 263: The method of any one of embodiments 1 to 262, wherein the subject has a family history of a neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic.

[0413] Embodiment 264: The method of any one of embodiments 1 to 263, wherein the subject has a genetic predisposition to neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic.

[0414] Embodiment 265: The method of any one of embodiments 1 to 264, wherein the subject has tested positive for a biomarker indicating presence of or predisposition to a neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic.

[0415] Embodiment 266: The method of any one of embodiments 1 to 259 or 261 to 265, wherein the subject has cognitive impairment.

[0416] Embodiment 267: The method of any one of embodiments 1 to 259 or 261 to 265, wherein the subject has mild, moderate, or severe cognitive impairment.

[0417] Embodiment 268: The method of any one of embodiments 1 to 259 or 261 to 265, wherein the subject has mild cognitive impairment.

[0418] Embodiment 269: The method of any one of embodiments 1 to 259 or 261 to 265, wherein the condition is cognitive impairment.

[0419] Embodiment 270: The method of any one of embodiments 1 to 259 or 261 to 265, wherein the condition is mild, moderate, or severe cognitive impairment.

[0420] Embodiment 271 : The method of any one of embodiments 1 to 259 or 261 to 265, wherein the condition is mild cognitive impairment.

[0421] Embodiment 272: The method of any one of embodiments 1 to 268, wherein the condition is a neurodegenerative disease.

[0422] Embodiment 273: The method of any one of embodiments 1 to 268, wherein the condition is a disease precursor or condition that predisposes the subject to develop a neurodegenerative disease.

[0423] Embodiment 274: The method of embodiment 272 or 273, wherein the neurodegenerative disease selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease, Huntington’s disease, vascular disease dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, tangle-predominant senile dementia, Pick's disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam parkinsonism-dementia complex, FTDP-17, Lytico-Bodig disease, multiple sclerosis, and traumatic brain injury (TBI), and combinations thereof.

[0424] Embodiment 275: The method of any one of embodiments 1 to 268, wherein the condition is a symptom associated with Alzheimer's disease (AD), Parkinson’s disease,Huntington’s disease, vascular disease dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, tangle-predominant senile dementia, Pick's disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam parkinsonism-dementia complex, FTDP-17, Lytico-Bodig disease, multiple sclerosis, or traumatic brain injury (TBI), or combinations thereof.

[0425] Embodiment 276: The method of any one of embodiments 1 to 268, wherein the condition is Alzheimer's disease or a symptom associated with Alzheimer’s disease.

[0426] Embodiment 277 : The method of any one of embodiments 1 to 268, wherein the condition is Parkinson's disease or a symptom associated with Parkinson's disease.

[0427] Embodiment 278: The method of any one of embodiments 1 to 268, wherein the condition is amyotrophic lateral sclerosis or a symptom associated with amyotrophic lateral sclerosis.

[0428] Embodiment 279: The method of any one of embodiments 1 to 278, wherein the subject is a human subject.

[0429] Embodiment 280: The method of any one of embodiments 1 to 279, wherein the subject is an adult.

[0430] Embodiment 281: The method of any one of embodiments 1 to 279, wherein the subject is a child.

[0431] Embodiment 282: The method of any one of embodiments 1 to 279, wherein the subject is at least 50 years old, at least 60 years old, at least 70 years old, or at least 80 years old.

[0432] The present invention is illustrated by the following examples. It is to be understood that the particular example, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the invention as set forth herein.EXAMPLESExample 1: Evidence for Lumacaftor as a Preventative Treatment for Alzheimer’s Disease and Dementia

[0433] Z-LaP Tracker, a deep neural network utilizing DeepLabCut, quantifies and measures 25 different behaviors of zebrafish larvae, providing insights into the effects of various classes of drugs. Zebrafish larvae are administered drugs of interest and then shown a presentation including auditory and visual stimuli. Their behavior is recorded using a camera and analyzed using deep learning models. The behavioral assay setup and presentation contents are summarized in Figure 1. Larvae respond uniquely to different classes of drugs, and CNIs — such as CsA, FK506, and pimecrolimus — elicit a specific response marked by an increase in baseline and resting activity, decreases in habituation, increases in excitability, decreases in optomotorresponses to red moving lines, and increases in scoot and burst behaviors. It is hypothesized that non-CNI drugs that generate a similar response in Z-LaP Tracker can be considered CNI-like and therefore may also have promise treating or preventing AD and dementia.

[0434] Surprisingly, lumacaftor produced an extremely CNI-like profile in Z-LaP Tracker, mirroring the behavioral changes typically induced by CNIs. Although lumacaftor had not been previously tested in Z-LaP Tracker and does not have obvious links to CNIs, further analysis highlights notable behavioral and biological similarities. In Z-LaP Tracker, lumacaftor elicits a highly CNI-like behavioral profile, marked by increases in activity, excitability, and scoot and burst behaviors, and decreases in habituation and optomotor response to red moving lines (Figures 2 and 3). Lumacaftor also prompts a distinctive swimming pattern produced also by CNIs (Figure 4). Additionally, co-administration of lumacaftor with CsA (a CNI) results in additive synergy, amplifying behavioral changes to a magnitude beyond those observed with either drug alone (Figure 5). Lastly, a comparison of lumacaftor with two large drug libraries (Tocriscreen and Cayman) revealed its behavioral profile significantly clusters with high with other CNIs, including CsA, FK506, and pimecrolimus. Lumacaftor’s CNI-like properties, favorable safety profile, and synergy with CsA and FK506 suggest that lumacaftor, alone or in combination with a CNI, could serve as a highly effective preventive treatment for AD and dementia.Results

[0435] Zebrafish larvae, 5 days post-fertilization, are placed individually into wells and exposed to different treatments: DMSO (control); FK506 (tacrolimus) 5 pM; FK506 10 pM; Lumacaftor 20 pM; Lumacaftor 30 pM; Lumacaftor 20 pM & FK506 5 pM; Lumacaftor 30 pM & FK506 5 pM (Figure 2). A second experiment evaluated DMSO (control); CsA (cyclosporin A) 5 pM; CsA 10 pM; Lumacaftor 10 pM; Lumacaftor 20 pM; Lumacaftor 10 pM & CsA 5 pM; Lumacaftor 10 pM & CsA 10 pM; Lumacaftor 20 pM & CsA 5 pM; Lumacaftor 20 pM & CsA 10 pM (Figure 3). After 3 initial hours of drug exposure, larvae are shown a 3-hour PowerPoint Presentation. The presentation includes 10, 18-minute slides containing visual and auditory stimuli. Throughout the presentation the larvae are photographed, their positions then estimated using Z-LaP Tracker — a deep-neural network built upon DeepLabCut. Z-LaP Tracker (Figure 1) uses the larval positioning to calculate 25 behaviors for each larva, including activity, optomotor response, startle, and excitability. Over 3000 larvae were exposed to the treatments in this study.

[0436] Lumacaftor elicits similar behavioral effects as CNIs (Figures 2 and 3). As previously described, this is marked by increases in baseline and resting activity, decreases in habituation, increases in excitability, decreases in optomotor responses to red moving lines, and increases in scoot and burst behaviors compared to the DMSO control. Furthermore, lumacaftorcombined with CsA produced a stronger behavioral response than either drug administered alone. Lumacaftor 30 pM + FK5065 pM produced the largest behavioral response, demonstrating dosedependency and the drugs’ statistically significant synergy.

[0437] Comparing lumacaftor and lumacaftor combinations with FK506 or CsA to two large drug libraries in Java Tree View revealed clustering of lumacaftor to other CNIs. Cluster plots were computed using Euclidean distance and complete-linkage. The first library explored was the Cayman Chemical FDA-approved Drug Library, containing 876 compounds. Lumacaftor clustered with 0.84 correlation to all the other CNIs in the library — pimecrolimus, FK506, and CsA. In the second drug library, the Tocriscreen FDA- Approved Drugs Library, containing 190 compounds, lumacaftor 20 pM clustered directly next to CsA 10 pM and FK506, the only CNIs in the library, with high correlation. Furthermore, combinations of lumacaftor with CsA also demonstrated a CNI-like behavioral profile. This statistical method of evaluating Z-LaP Tracker behaviors suggests that lumacaftor elicits a highly CNI-like response.

[0438] To reveal how lumacaftor and CNIs affect resting behavior in larvae, Z-LaP Tracker, and R plotly were employed for dynamic 3D visualization of larval movement. Spatial coordinates (X, Y) and temporal markers (image / time) were used to reconstruct movement patterns in three-dimensional space, where speed variations were conveyed with a rainbow color gradient. During Period 15, a period without visual or acoustic stimuli, larval activity is expected to be limited, as displayed for DMSO in Figure 4. CNIs like CsA elicit increased activity, where larvae are swimming in fast, circular motions around the peripheral of the well. Higher doses of CsA or FK506 amplified this behavior, causing larvae to swim more laps at a faster pace. Lumacaftor produced a highly CNI-like swimming pattern, and combinations of CsA with lumacaftor synergized, also generating a CNI-like profile.

[0439] These collective results from Z-LaP Tracker indicate that lumacaftor is CNI-like, and that combinations of lumacaftor with FK506 or CsA are synergistic. This provides evidence that lumacaftor or lumacaftor combinations with CNIs may be effective preventative treatments for AD and dementia.Discussion

[0440] This study sought to identify nontoxic alternatives to CNIs using Z-LaP Tracker. CNIs such as CsA and FK506 have been suggested as potential therapeutics for AD and dementia. Lumacaftor produced a highly CNI-like behavioral profile in Z-LaP Tracker, suggesting that lumacaftor may share mechanistic similarities to CNIs and therefore may also be protective against neurodegeneration. Furthermore, combining lumacaftor with a reduced dose of FK506 or CsA produced a behavioral response comparable to that of a high dose of FK506 or CsA alone,providing evidence that lumacaftor and a CNT can be co-administered to maximize efficacy while mitigating toxicity concerns related to CNIs.

[0441] While lumacaftor’ s known function is as a CFTR corrector, its CNI-like behavioral profile in Z-LaP Tracker suggests that lumacaftor may have some activity in the calcineurin-NFAT pathway. A literature review and IPA Pathway Analysis reveal that lumacaftor has multiple potential mechanistic connections to the CNI pathway (Figure 8). Lumacaftor has been found to decrease levels of intracellular Ca2+and decrease release of Ca2+from the ER (Yanda MK, et al., J Biol Chem. 2018 Jul 20;293(29):l 1513-11526). In the calcineurin-NFAT pathway, elevated intracellular calcium binds to calmodulin, undergoing a conformational change, allowing for the activation of calcineurin. Lumacaftor may be able to inhibit the calcineurin-NFAT through decreasing Ca2+. Elevated Ca2+is also a hallmark of AD and dementia, with increased Ca2+from the ER causing compensatory changes impacting long-term potentiation and long-term depression synaptic mechanisms. This promotes neuroinflammatory atrophy, contributing to memory loss. Consequently, lumacaftor’ s ability to decrease intracellular Ca2+provides multiple mechanisms by which lumacaftor may act in the calcineurin-NFAT pathway and treating or preventing AD pathology.

[0442] Lumacaftor inhibits HSP90 (Yanda MK, et al., J Biol Chem. 2018 Jul 20;293(29): 11513- 11526), a molecular chaperone and key regulator of proteostasis in physiological and stress conditions, likely by increasing its rate of degradation. HSP90 stabilizes and helps maintain the functional conformation of calcineurin, allowing for its binding with calmodulin. Consequently, lumacaftor may inhibit the calcineurin-NFAT pathway by destabilizing calcineurin via antagonizing HSP90. HSP90 assists proteins in their proper folding and assembly, protecting against aggregation and facilitating degradation. HSP90 also regulates HSF-1, the leader of the heat shock response, inducing other heat shock proteins such as HSP70. In neurodegenerative disorders such as AD and dementia, HSP90 suppresses the toxicity of aberrant proteins and allows for the functional stability and accumulation of toxic aggregates, contributing to disease pathology (Luo W, et al., BMC Neurosci. 2008 Dec 3;9 Suppl 2(Suppl 2):S7). Inhibition of HSP90 in cellular and mouse tauopathy models promotes time- and dosedependent elimination of tau aggregates. Furthermore, HSP90 inhibition increases levels of HSP70, promoting tau solubility, decreasing the propensity of A aggregation, and targeting amyloid precursor protein (APP) clearance. Through the calcineurin-NFAT pathway and other mechanisms, lumacaftor’ s inhibition of HSP90 suggests a potential method for preventing dementia and AD.

[0443] Lumacaftor has also been shown to significantly decrease caspase-3 (C ASP-3) activity (Yanda MK, et al., J Biol Chem. 2018 Jul 20;293(29): 11513-11526). CASP-3 belongs to a family of proteases regulating apoptosis where CASP-3 is a key mediator of apoptosis in neuronal cells. CASP-3 can activate calcineurin through its cleavage, contributing to IL-2 release and T cell activation. Furthermore, calcineurin can influence CASP-3 activity and its apoptotic cascade (Springer JE, et al., J Neurosci. 2000 Oct 1 ;20(19):7246-51). This suggests that lumacaftor' s ability to decrease CASP-3 activity may contribute to inhibition of the calcineurin-NFAT pathway. CASP-3 is implicated in the early progression of AD, as CASP-3 can cleave APP into amyloidogenic fragments. CASP-3 is found in elevated levels in the postsynaptic density fractions in people with AD and has been found to trigger early synaptic dysfunction in AD models. Different groups have suggested that targeting caspases could be a promising therapeutic strategy for mitigating neuronal loss and slowing the progression of AD by preventing tau and AP-induced neurotoxicity (Wojcik, P., et al.. Mol Neurobiol 61, 4834-4853 (2024). Lumacaftor’s ability to reduce CASP-3 activity may offer a potential therapeutic avenue for mitigating synaptic dysfunction and neuronal loss in Alzheimer’s disease by disrupting key apoptotic and neurotoxic pathways, including through its modulation of the calcineurin-NFAT pathway.

[0444] Lumacaftor may also have a more direct role inhibiting the calcineurin-NFAT pathway. CB-DOCK2, an online platform for predicting protein-ligand interactions, was utilized to predict lumacaftor’s binding affinity to targets of CNIs. CsA and voclosporin, another CNI, both bind to cyclophilin A, forming a complex which inhibits calcineurin. FK506 and pimecrolimus bind to FKBP-12, forming a complex which inhibits calcineurin. Consequently, lumacaftor’s interactions with cyclophilin A, FKBP-12, and calcineurin were explored. An AutoDock Vina Score lower than -8.0 kcal / mol predicts strong binding affinity, and interestingly, CB-DOCK2 calculated that lumacaftor’s Vina Scores with calcineurin, FKBP-12, and cyclophilin A were -11.1, -8.4, and -8.8 kcal / mol, respectively (Figure 7). This indicates that lumacaftor may directly bind and inhibit direct targets of CNIs, including calcineurin, cyclophilin A, and / or FKBP-12.

[0445] Beyond the calcineurin-NFAT pathway or CFTR correction, there is a growing body of evidence suggesting that lumacaftor may be an effective treatment for neurodegenerative diseases such as AD and dementia. ER stress occurs under certain physiological conditions when the ER partially folds, misfolds, or fails to fold proteins. Ribosomes on the ER are responsible for one-third of total protein production, and the ER is considered “the major store” for Ca2+in the cell, therefore ER stress can have many adverse biological repercussions. To combat ER stress, the unfolded protein response (UPR) triggers a signaling cascade to expel misfolded / unfolded'llproteins during early stages of ER stress or induce cell death pathways in during later stages of ER stress. Aggregates of A|3 accentuate ER stress and disrupt cellular homeostasis. It is hypothesized that A drives ER stress in early stages of AD and maladaptive UPR neuronal cell death in later stages of AD. In a model of ER stress induced by thapsigargin in neuroblastoma cells, lumacaftor demonstrated a significant ability to decrease intracellular stress, improve protein folding, and normalize UPR activation (Pecoraro M, et al., Curr Issues Mol Biol. 2024 Aug 24;46(9):9342-9358). This signifies an ability for lumacaftor to restore homeostasis, protect against neurotoxic aggregates, and reverse cellular damage which may be caused by neurodegenerative diseases such as AD.

[0446] While lumacaftor was originally hypothesized to promote the correct folding of CFTR by a CFTR-specific mechanism, new evidence suggests that lumacaftor may work by a general mechanism on misfolded proteins, with potential applications to AD and dementia. Lumacaftor demonstrated the ability to counteract UPR activation due to stressful ER conditions, significantly reducing the expression of Grp78 / BiP, the signaling regulator of ER stress which binds to Ca2+, ATF4, ATF6, pPERK, and CHOP — key pro-inflammatory promoters of the UPR pathway (Pecoraro M, et al., Cun-Issues Mol Biol. 2024 Aug 24;46(9):9342-9358). Through its activity suppressing the UPR, lumacaftor can lessen intracellular and mitochondrial stress with the reduction of reactive oxygen species (ROS) and superoxide dismutase III (SODIII) expression (Pecoraro M, et al., Curr Issues Mol Biol. 2024 Aug 24;46(9):9342-9358). Furthermore, lumacaftor promotes the restoration of normal calcium homeostasis perturbed by ER stress, reducing free Ca2+levels and lowering SERCA II expression (Pecoraro M, et al., Curr Issues Mol Biol. 2024 Aug 24;46(9):9342-9358). This evidence demonstrates that lumacaftor can restore physiological conditions back to equilibrium even under high levels of ER stress.

[0447] Beyond its effects on ER stress, lumacaftor also plays a role in mitigating the inflammatory response associated with protein misfolding. By inhibiting the nuclear factor-kB (NF-kB)ZiKKa pathway, an established pathway in AD pathology, lumacaftor reduces inflammation triggered by oxidative stress, thereby preventing the transcription of pro-inflammatory cytokines. Lumacaftor’ s downstream inhibition of pro-inflammatory cytokines provided a mechanistic connection to CNIs, which also target cytokine inhibition. Given that AD is largely caused by misfolded proteins such as Ap and tau, which leads to ER stress, lumacaftor may be able to treat neurodegeneration by lessening the effects of toxic proteins. Lumacaftor’ s ability to modulate multiple stress pathways, including oxidative stress, calcium dysregulation, and pro-inflammatory cytokines, supports its therapeutic application to neurodegenerative diseases such as AD.

[0448] Guanosine monophosphate reductase receptor 1 (GMPR1) is a novel potential therapeutic target for AD, and lumacaftor is an ideal inhibitor of the receptor. The GMPR gene increases in expression with the progression of AD, and its product, GMPR1 inhibits both the AMPK and adenosine receptors (A1 / A2) pathways. Elevated AMPK levels are associated with tau accumulation and A0 aggregation, while elevated adenosine is observed in the brain of AD patients and increases levels of tau phosphorylation. The AMPK signaling pathway is closely associated with the pathogenesis of AD, as it regulates energy homeostasis and neuronal health, and adenosine A2A receptors are pathologically altered in AD and tauopathies. Furthermore, calmodulin binds to the A2A receptor in a calcium-dependent manner, suggesting that A2A receptor inhibition could decrease calcineurin activity, connecting lumacaftor to CNIs. In a comprehensive screening of 1,174 approved therapeutics, lumacaftor emerged as an ideal inhibitor of GMPR1 (Liu H, et al., Sci Rep. 2018 Feb 9;8(1):2759). Subsequent in vivo studies demonstrated that a 20-day oral administration of lumacaftor in AD model mice resulted in a significant slowdown of P-amyloid accumulation and a near-complete elimination of tau phosphorylation in both parietal and temporal lobes and the hippocampus (Liu H, et al., Sci Rep.2018 Feb 9;8(1):2759). These findings highlight the potential of lumacaftor as a therapeutic for AD, through the inhibition of GMPR1 and the modulation of critical pathways involved in AD progression.

[0449] Lumacaftor has shown promise in addressing neurodegeneration associated with myocardial infarction (MI), supporting its role in treating or preventing broader neuroinflammation and neurodegeneration. MI causes neurodegeneration with decreased hippocampal dendrite length, spine density, neuronal CFTR expression, and microglial activation. Inflammatory cytokine expression such as IL-ip, IL-8, IL-33, chemokine ligand 20, and IL-6 increase, downregulating CFTR expression. In a murine model, CFTR inhibition was found to decrease PSD-95, a postsynaptic density protein promoting the maturation and strength of synapses (Vanherle L, et al., EBioMedicine. 2022 Dec;86: 104384). Lumacaftor restored CFTR expression in the hippocampus, restored levels of PSD-95, decreased neuronal apoptosis due to oxidative stress, and decreased inflammatory cytokine expression. Lumacaftor improved neuronal architecture while normalizing novel object recognition, a cognitive function impaired by MI. Lumacaftor demonstrated high levels of efficacy even when delivered to mice 22 weeks post-MI, suggesting a large therapeutic window (Vanherle L, et al., EBioMedicine. 2022 Dec:86: 104384). This highlights lumacaftor’s ability to restore cognitive function following events causing neurodegeneration.

[0450] In humans, postmortem analysis revealed reduced expression of CFTR in the hypothalamus of AD patients (Lahousse SA, et al., J Alzheimers Dis. 2003 Dec;5(6):455-62), suggesting that CFTR may be implicated in early AD progression (Ishii M and ladecola C. Cell Metab. 2015 Nov 3;22(5):761 -76). Neuroimaging of CF patients have revealed significant structural and functional brain changes. Increased gray matter density, indicative of tissue injury, was observed in the hippocampus, cerebellum, amygdala, insula, basal forebrain, and the frontal and prefrontal cortices. These brain regions control cognition, memory, and mood regulation, all implicated in AD. Additionally, reduced T2-relaxation values, markers of glial activation, edema, oxidative injury, and neuronal loss, were found in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum. This suggests that stress and hypoxia in CF contribute to neuroinflammation and neurodegeneration in similar regions as to AD.

[0451] Other studies have shown that CF patients exhibit measurable cognitive deficits, with individuals averaging 44 years of age demonstrating memory performance comparable to that of 69.7-year-old patients with mild cognitive impairment (A. Imtiaz, et al., J. Cyst Fibres, Vol 23, Suppl. 1, 2024,S38-S39). While CF patients had a life expectancy of around 30 years in the 1990s, advances in care now allow many to live into their 70s and 80s. This only recent increase means there has been limited, but increasing, opportunity to study age-related conditions like AD and dementia in CF patients. As more CF patients reach older ages, data on the relationship between CFTR dysfunction and neurodegeneration may become increasingly available. Furthermore, CF therapeutics such as lumacaftor may correct the structural and physiological abnormalities observed in the CF brain, potentially preventing the development of AD and dementia. CF-related brain alterations provide a compelling translational link to the pathogenesis of AD and reinforce lumacaftor’ s potential to reverse and prevent neuronal damage from neurodegenerative diseases.

[0452] Given the evidence that CNIs and CNI-like drugs may have a therapeutic potential to decrease AD prevalence, we hypothesize that combining CNIs with CNI-type drugs such as lumacaftor may augment their therapeutic potential in preventing AD and dementia. Z-LaP Tracker data suggests that lower doses of lumacaftor and FK506 or CsA, when administered in combination, elicit a greater magnitude behavioral response than high doses of either compound administered independently (Figure 5). This synergy could be explained by the potential complementary mechanisms by which FK506 / CsA and lumacaftor inhibit the calcineurin-NFAT pathway. Ingenuity Pathway Analysis predicts confidently that lumacaftor inhibits the downstream targets of CNIs FK506 and CsA, and that co-administration of lumacaftor with each CNI yields higher predicted levels of inhibition (Figure 8). Beyond the calcineurin-NFATpathway, lumacaftor and CNTs may target distinct etiological factors of AD, further supporting their potential for co- administration. Lastly, the synergy observed between lumacaftor and CNIs may allow for reduced doses of CNIs to be delivered, meaningfully lowering toxicity.

[0453] Lumacaftor is a strong inducer of Cytochrome P4503 A (CYP3 A). CYP3 A belongs to a superfamily of monooxygenases, primarily found in the liver, that are critical in the metabolism and breakdown of endogenous compounds and drugs. CYP3A specifically is responsible for the breakdown of half of all FDA approved drugs. Consequently, lumacaftor administration can significantly decrease exposure of drugs which are CYP3A substrates and therefore co-administration with CYP3A substrates is generally not recommended (Talamo Guevara M and McColley SA, Expert Opin Drug Saf. 2017 Nov;16(ll):1305-1311). CNIs such as CsA, FK506, sirolimus, and voclosporin are all substrates of CYP3 A, and because steady levels of CNI exposure is required for the prophylaxis of organ rejection, co-administration is typically avoided. However, co-administration of lumacaftor with a CNI may offer therapeutic advantages, rather than posing a risk, in the context of treating or preventing AD and dementia. Because lumacaftor enhances the metabolism of CNIs when co-administered, combining lumacaftor with a CNI may help reduce CNI-associated toxicities while still maintaining synergistic therapeutic effects. Case studies of liver transplant recipients concurrently on a CFTR modulator and FK506 suggests that both treatments can be co-administered while maintaining steady CNI exposure (Smith M, et al., I Cyst Fibres. 2022 Ian;21(l):e8-el0), and other reports indicate that lumacaftor and FK506 can be co-administered safely and efficaciously (Chouchane I, et al., Clin Case Rep.2019 Feb 17;7(4):616-618). Consequently, while FDA labels recommend against the co-administration of lumacaftor with CNIs, this guidance should not apply to a novel combination of the therapies purposed for the prevention of AD and dementia.

[0454] The complete disclosure of all patents, patent applications, and publications, and electronically available material cited herein are incorporated by reference. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations are to be understood there from. The invention is not limited to the exact details shown and described, for variations obvious to one skilled in the art will be included within the invention defined by the claims.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a condition, comprising administering to a subject in need thereof a therapeutically-effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) an agent, or a pharmaceutically acceptable salt thereof, that is(a) a CYP3A4 inducer; and / or(b) a P-glycoprotein (P-gp) inhibitor.

2. The method of claim 1 , wherein the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the agent, or the pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

3. The method of claim 2, wherein the therapeutic effect is synergistic.

4. The method of claim 2, wherein the therapeutic effect is additive.

5. The method of claim 1, wherein the agent is a CYP3A4 inducer and a P-glycoprotein (P-gp) inhibitor.

6. The method of any one of claims 1 to 5, wherein the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

7. The method of any one of claims 1 to 6, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the agent is lumacaftor, or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1 to 7, wherein the agent, or the pharmaceutically acceptable salt thereof is selected from a compound of Schedule A.

10. The method of any one of claims 1 to 9, wherein the CYP3A4 inducer increases CYP3A4 activity and / or increases CYP3A4 expression.

11. The method of any one of claims 1 to 10, wherein the P-gp inhibitor inhibits P-gp activity and / or decreases P-gp expression.

12. The method of any one of claims 1 to 11, wherein the calcineurin inhibitor and the agent are each administered orally.

13. The method of any one of claims 1 to 11, wherein the calcineurin inhibitor is administered intravenously and the agent is administered orally.

14. The method of any one of claims 1 to 11, wherein the calcineurin inhibitor is administered orally and the agent is administered intravenously.

15. The method of any one of claims 1 to 11 , wherein the calcineurin inhibitor and the agent are each administered intravenously.

16. The method of any one of claims 1 to 15, wherein the calcineurin inhibitor and the agent are sequentially administered.

17. The method of any one of claims 1 to 1 , wherein the calcineurin inhibitor and the agent are concurrently administered.

18. The method of any one of claims 1 to 17, wherein the calcineurin inhibitor is administered once, twice, or three times a day.

19. The method of any one of claims 1 to 18, wherein the agent is administered once, twice, or three times a day.

20. The method of any one of claims 1 to 19, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 0.075mg / kg / day to about 0.3 mg / kg / day administered in one or two daily doses.

21. The method of any one of claims 1 to 19, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg to about 25 mg administered in one or two daily doses.

22. The method of any one of claims 1 to 19, wherein the calcineurin inhibitor is tacrolimus, and wherein the therapeutically effective amount is about 3 mg, about 5 mg, about 7.5 mg, or about 10 mg administered in one or two daily doses.

23. The method of any one of claims 1 to 22, wherein the agent is lumacaftor, and the therapeutically effective amount is a dose of about 100 mg / day to about 800 mg / day administered in one or two daily doses.

24. The method of any one of claims 20 to 23, wherein the therapeutic dose of tacrolimus is lower compared with a therapeutic dose of tacrolimus when administered in the absence of lumacaftor.

25. The method of claim 24,wherein the therapeutic dose of tacrolimus is (i) 0.3 mg / kg / day in the absence of lumacaftor; and (ii) 0.2 mg / kg / day, 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose amount of tacrolimus is (i) 0.2 mg / kg / day in the absence of lumacaftor; and (ii) 0.15 mg / kg / day, 0.1 mg / kg / day, or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.15 mg / kg / day in the absence of lumacaftor; and (ii) 0.1 mg / kg / day or 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.1 mg / kg / day in the absence of lumacaftor; and (ii) 0.075 mg / kg / day when administered in combination with lumacaftor; orwherein the therapeutic dose of tacrolimus is (i) 0.075 mg / kg / day in the absence of lumacaftor; and (ii) 0.05 mg / kg / day when administered in combination with lumacaftor.

26. The method of any one of claims 1 to 8, or 10 to 25. wherein lumacaftor is administered at a first daily dose and tacrolimus is administered at a second daily dose, wherein the first daily dose is about 5 to about 200 times higher than the second daily dose.

27. The method of any one of claims 1 to 26, wherein the administering results in reduced systemic toxicity of the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in the subject as compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

28. The method of claim 27, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

29. The method of claim 27 or 28. wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

30. The method of claim 27 or 28, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 to Grade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

31. The method of any one of claims 1 to 30, wherein the combination provides a greater therapeutic effect as compared to a therapeutic effect observed in a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

32. The method of claim 31, wherein the therapeutic effect is improvement in memory, orientation, judgement / problem solving, motivation, community affairs, interest in hobbies, or personal care, or combinations thereof.

33. The method of claim 31 , wherein the therapeutic effect is reduction in amyloid-beta plaque levels, reduction in tau protein levels, a decrease in neurofilament light chain levels, or combinations thereof.

34. The method of claim 31, wherein the therapeutic effect is improvement or reduction of tremors or bradykinesia or a combination thereof.

35. The method of any one of claims 31 to 34, wherein the therapeutic effect is greater by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

36. The method of any one of claims 1 to 35, wherein the therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is lower compared to a therapeutically-effective amount of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, when administered to a control subject in absence of the agent.

37. The method of any one of claims 1 to 36, wherein the administering results in increased central nervous system concentration of the calcineurin inhibitor.

38. The method of claim 37, wherein the central nervous system concentration of the calcineurin inhibitor is higher compared to a control subject administered the calcineurin inhibitor or the pharmaceutically acceptable salt thereof in absence of the agent.

39. The method of claim 38, wherein the central nervous system concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, is increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

40. The method of any one of claims 1 to 39, wherein the administering results in decreased peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, in the subject as compared to a control subject administered the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in absence of the agent.

41. The method of claim 40, wherein decreasing the peripheral concentration of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof in the subject reduces systemic toxicity in the subject.

42. The method of claim 41, wherein the systemic toxicity is nephrotoxicity, hypertension, infection, diabetes, dyslipidemia, hyperkalemia, or a combination thereof.

43. The method of claim 41 or 42, wherein the systemic toxicity is reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

44. The method of claim 41 or 42, wherein the systemic toxicity is reduced from Grade 4 to Grade 3, or Grade 4 to Grade 2, or Grade 4 to Grade 1, or Grade 3 to Grade 2, or Grade 3 toGrade 1 , or Grade 2 to Grade 1 as determined by Common Terminology Criteria for Adverse Events v6.0 (CTCAE v6.0).

45. The method of any one of claims 1 to 44, wherein the administering decreases peripheral concentration (e.g., plasma, blood or tissue concentration) of the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

46. A method of treating a condition, comprising administering to a subject a therapeutically- effective amount of a combination comprising:(i) tacrolimus, or a pharmaceutically acceptable salt thereof; and(ii) lumacaftor, or a pharmaceutically acceptable salt thereof.

47. A method of treating a condition, comprising administering to a subject a therapeutically- effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof: and(ii) an agent, or a pharmaceutically acceptable salt thereof, that exhibits calcineurin inhibitor- like properties.

48. The method of claim 47, wherein the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

49. The method of claim 47 or 48, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

50. The method of any one of claims 47 to 49, wherein the agent is lumacaftor, or a pharmaceutically acceptable salt thereof.

51. A method of treating a condition, comprising administering to a subject a therapeutically- effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) a cystic fibrosis transmembrane conductance regulator (CFTR) modulating compound, or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein the calcineurin inhibitor, or the pharmaceutically acceptable salt thereof, and the CFTR modulating compound, or a pharmaceutically acceptable salt thereof, have a synergistic or additive therapeutic effect.

53. The method of claim 51, wherein the calcineurin inhibitor is tacrolimus (FK506) or a derivative thereof, cyclosporin (CsA), voclosporin, pimecrolimus, or ascomycin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

54. The method of any one of claims 51 to 53, wherein the calcineurin inhibitor is tacrolimus, or a pharmaceutically acceptable salt thereof.

55. The method of any one of claims 51 to 54, wherein the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, is a CFTR potentiator, corrector, dual-acting potentiator and corrector, or a combination thereof.

56. The method of any one of claims 51 to 54, wherein the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, is a CFTR corrector.

57. The method of any one of claims 51 to 54, wherein the CFTR modulating compound, or the pharmaceutically acceptable salt thereof, comprises calcineurin inhibitor-like activity.

58. The method of any one of claims 51 to 54, wherein the CFTR modulating compound is a compound from Schedule B.

59. The method of any one of claims 51 to 54, wherein the CFTR modulating compound is lumacaftor, vanzacaftor, tezacaftor, deutivacaftor, elexacaftor, or ivacaftor, or a pharmaceutically acceptable salt thereof, or a combination thereof.

60. The method of any one of claims 51 to 54, wherein the CFTR modulating compound is lumacaftor, or the pharmaceutically acceptable salt thereof.

61. A method of treating a condition, comprising administering to a subject a therapeutically- effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) an agent from Schedule A or Schedule B, or a pharmaceutically acceptable salt thereof.

62. A method of treating a condition, comprising administering to a subject a therapeutically- effective amount of a combination comprising:(i) a calcineurin inhibitor, or a pharmaceutically acceptable salt thereof; and(ii) an agent, or a pharmaceutically acceptable salt thereof, that(a) increases a therapeutic effect;(b) reduces systemic toxicity;(c) increases central nervous system concentration; and / or(d) reduces a therapeutically-effective dose;of the calcineurin inhibitor or a pharmaceutically acceptable salt thereof.

63. The method of any one of claims 1 to 62, wherein treating the condition comprises delaying or arresting symptom progression (e.g., cognitive decline).

64. The method of any one of claims 1 to 62, wherein treating the condition comprises delaying or arresting biomarker movement.

65. A method of reducing systemic toxicity in a subject who is being treated with tacrolimus, or a pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

66. A method of decreasing a therapeutically-effective amount of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject who is receiving tacrolimus or the pharmaceutically acceptable salt thereof, comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

67. A method of increasing central nervous system concentration of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

68. A method of decreasing peripheral concentration of tacrolimus, or a pharmaceutically acceptable salt thereof, in a subject comprising administering to the subject lumacaftor, or a pharmaceutically acceptable salt thereof.

69. The method of any one of claims 1 to 68, wherein the subject is cognitively asymptomatic.

70. The method of any one of claims 1 to 69, wherein the subject has a risk factor for developing a neurodegenerative disease, disorder, or condition.

71. The method of claim 70, wherein the risk factor is family history, genetic, presence of absence of a biomarker associated with a neurodegenerative disease, disorder, or condition, the subject’s age, or the subject’s current or previous participation in high-impact activities.

72. The method of any one of claims 1 to 71, wherein the subject has a family history of a neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic.

73. The method of any one of claims 1 to 72, wherein the subject has a genetic predisposition to neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic.

74. The method of any one of claims 1 to 73, wherein the subject has tested positive for a biomarker indicating presence of or predisposition to a neurodegenerative disease, condition, or disorder, optionally wherein the subject is cognitively asymptomatic.

75. The method of any one of claims 1 to 68 or 70 to 74, wherein the subject has cognitive impairment.

76. The method of any one of claims 1 to 68 or 70 to 74, wherein the condition is mild cognitive impairment.

77. The method of any one of claims 1 to 76, wherein the condition is a neurodegenerativedisease.

78. The method of any one of claims 1 to 76, wherein the condition is a disease precursor or condition that predisposes the subject to develop a neurodegenerative disease.

79. The method of claim 77 or 78, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease (AD), Parkinson's disease, Huntington’s disease, vascular disease dementia, frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Lewy body dementia, tangle-predominant senile dementia, Pick’s disease (PiD), argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), other motor neuron diseases, Guam parkinsonism-dementia complex, FTDP-17, Lytico-Bodig disease, multiple sclerosis, and traumatic brain injury (TBI), and combinations thereof.

80. The method of any one of claims 1 to 76, wherein the condition is Alzheimer's disease or a symptom associated with Alzheimer’s disease.

81. The method of any one of claims 1 to 76, wherein the condition is Parkinson's disease or a symptom associated with Parkinson's disease.

82. The method of any one of claims 1 to 76, wherein the condition is amyotrophic lateral sclerosis or a symptom associated with amyotrophic lateral sclerosis.

83. The method of any one of claims 1 to 82, wherein the subject is a human subject.

84. The method of any one of claims 1 to 83, wherein the subject is at least 50 years old, at least 60 years old, at least 70 years old, or at least 80 years old.

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