OA20813A - Methods of administering voxelotor - Google Patents

Abstract

Provided herein are methods of using voxelotor for the treatment of sickle cell disease in patients also having severe hepatic impairment. Also provided herein are methods for administering voxelotor and avoiding or lessening adverse drug interactions with a CYP3A4 inducer or inhibitor. Also provided herein are methods for avoiding interactions with voxelotor, a moderate CYP3A4 inhibitor.

Description

METHODS OF ADMINISTERING VOXELOTOR

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application daims the benefit under 35 U.S.C. §119(e) of United States 5 Provisional Application No. 62/937,706, filed November 19, 2019, and United States Provisional

Application No. 62/940,154, fîled November 25, 2019, each of which is hereby incorporated by reference in its entirety.

FIELD

[0002] Provided herein are methods for treating sickle cell disease using voxelotor in patients that also hâve severe hepatic impairment. Also provided herein are methods for administering voxelotor and avoiding or lessening adverse drug interactions, Also provided herein are methods for avoiding clinically signifïcant interactions with voxelotor, a moderate CYP3A4 inhibitor.

BACKGROUND

[0003] Voxelotor (also known as Oxbryta™ and formerly known as GBT440) is a small molécule allosteric modifier of hemoglobin-oxygen afïlnity useful for the treatment of sickle cell disease (SCD). Voxelotor can be administered orally. Voxelotor can increase heinoglobin’s affînity for oxygen, thereby stabilizing hemoglobin in the oxyhemoglobin State, which can lead 20 to inhibition of polymerization of sickle hemoglobin (HbS).

[0004] The major route of élimination of voxelotor îs by metabolism. In sickle cell patients with normal hepatic fonction, 1500 mg of voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis, indicating inhibition of HbS polymerization. In patient populations with severe, moderate, or miid hepatic impairment, drug dosages may or may not 25 need to be adjusted for such patients. Thus, there is a need for developing treatment suitable for

SCD patients who also hâve hepatic impairment.

[0005] Further, voxelotor is also a moderate inhibitor of cytochrome P450 (CYP)3A4, the most prévalent CYP enzyme in the liver, in humans. Accordingly, improved methods for administering voxelotor are needed to avoid or lessen potential adverse drug interactions.

SUMMARY

[0006] Provided herein includes a method of treating sickle cell disease in a patient in need thereof. The method comprises administering to a patient having sickle cell disease 500 mg to 1000 mg of voxelotor per day, wherein the patient also has severe hepatic impaîrment. Some embodiments provide for methods of treating sickle cell disease in a patient in need thereof, comprising administering to the patient 1000 mg of voxelotor per day, wherein the patient has severe hepatic impainnent.

[0007] Also provided herein are methods for administering voxelotor and avoiding or lessening adverse drug interactions. Also provided herein are methods for avoiding interactions with voxelotor, a moderate CYP3A4 inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 shows plots for mean (+SD) of whole blood voxelotor concentration-time profiles (pharmacokinetic évaluable population).

[0009] FIG. 2A, FIG. 2B, FIG. 2C, and FIG. 2D show plots for overlay of whole blood voxelotor concentration-time profile (pharmacokinetic full population) for hepatic impairment status of subjects being mild (FIG. 2A), moderate (FIG. 2B), severe (FIG. 2C), and severe with dose adjusted (FIG. 2D).

[0010] FIG. 3 shows plots for mean (+ SD) of plasma voxelotor concentration-time profiles (pharmacokinetic évaluation population).

[0011] FIG. 4A, FIG. 4B, FIG. 4C, and FIG. 4D show plots for overlay of plasma voxelotor concentration-time profile (pharmacokinetic full population) for hepatic impairment status of subjects being mild (FIG. 4A), moderate (FIG. 4B), severe (FIG. 4C), and severe with dose adjusted (FIG. 4D).

[0012] FIG. 5 shows forest plots of individual ratios of pharmacokinetics parameters of whole blood voxelotor by hepatic impairment status group (pharmacokinetic évaluable population).

[0013] FIG. 6 shows forest plots of individual ratios of pharmacokinetics parameters of plasma voxelotor by hepatic impairment status group (pharmacokinetic évaluable population).

[0014] FIG. 7 shows a forest plot to assess the effect of multiple doses of voxelotor on the pharmacokinetics of caffeine, S-warfarin, omeprazole, midazolam, and theîr métabolites.

[0015] FIG. 8 shows subject-level change from baseline in hemoglobin at week 24 in patients who completed 24 weeks of treatment. Approximately 82% of ali randomized patients 5 completed 24 weeks of treatment.

DETAILED DESCRIPTION

Définitions

[0016] Unless defîned otherwise, ail technical and scientific terms used herein hâve the same 10 meaning as is commonly understood by one of ordinary skill in the art. As used herein, the below terms hâve the following meanings unless specified otherwise. Any methods, devices and materials similar or équivalent to those described herein can be used in the practice of the compositions and methods described herein. The following définitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to I im it the scope of the 15 present disclosure. Ail references referred to herein are incorporated by reference in theîr entirety.

[0017] It is noted here that as used in this spécification and the appended daims, the singular fomis “a” “an” and “the” and the like inciude plural referents unless the context clearly dictâtes otherwise.

[0018] The term “about” or “approximately” means within ± 30%, 20%, 15%, 10%, 9%, 8%,

7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In some embodiments, “about” means ± 5% of a given value or range. In some embodiments, “about” means ± 4% of a given value or range. In some embodiments, “about” means ± 3% of a given value or range. In some embodiments, “about” means ± 2% of a given value or range. In some embodiments, “about” means ± 1% of a given value or range. In another embodiment, about means ± 0.5% of a given value or range. In some embodiments, “about” means ± 0.05% of a given value or range.

[0019] As used herein, the term “administration” refers to introducing an agent into a patient. For example, a therapeutic amount can be administered to the patient, which can be determined by the treating physician or the like. In some embodiments, an oral route of administration is 30 preferred. The related terms and phrases “administering” and “administration of,” when used in

connection with a compound or tablet (and grammatical équivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by selfadministration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. Administration entails delivery to the patient of the drug.

[0020] The term “dose” or “dosage” refers to the total amount of an active agent (e.g., voxelotor) administered to a patient in a single day (24-hour period). The desired dose can be administered once daily. In some embodiments, the desired dose may be administered in one, two, three, four or more sub-doses at appropriate întervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day. The terms “dose” and “dosage” are used interchangeably herein.

[0021] As used herein, where the mass of voxelotor is specified, for example, 500 mg, 1000 mg or 1500 mg of voxelotor, that amount corresponds to the mass of voxelotor in its free base fonn in a single tablet.

[0022] The term “hemoglobin” as used herein refers to any hemoglobin protein, including normal hemoglobin (Hb) and sickle hemoglobin (HbS).

[00231 The term “sickle cell disease” refers to diseases mediated by sickle hemoglobin (HbS) that results from a single point mutation in the hemoglobin (Hb). Non-limiting examples of sickle cell diseases include sickle cell anémia, sickle-hemoglobin C disease (HbSC), sickle betaplus-thalassaemia (HbS/β) and sickle beta-zero-thalassaemia (HbS/βΟ).

[0024] As used herein, “therapeutically effective amount” or “therapeutic amount” refers to an amount of a drug or an agent (e.g., voxelotor) that when administered to a patient suffering from a condition, will hâve the intended therapeutic effect, e.g., alleviation, amelioration, palliation or élimination of one or more manifestations of the condition in the patient. The full therapeutic effect does not necessarily occur by administration of one dose, and can occur only after administration of a sériés of doses and can be administered in one dose form or multiples thereof. For example, 1000 mg of the drug can be administered in a single 1000 mg strength tablet or two 500 mg strength tablets. As another example, 500 mg of the drug can be administered in a single 500 mg strength tablet. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of an agent, in the context of treating disorders related to

hemoglobin S, refers to an amount of the agent that alleviates, améliorâtes, palliâtes, or éliminâtes one or more manifestations of the disorders related to hemoglobin S in the patient.

[0025] As used herein, the term “pharmaceutically acceptable” refers to generally safe and non-toxic for in vivo, preferably human, administration.

[0026] As used herein, the term “patient” refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. A patient as described herein can be a human. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or juvénile. In some embodiments, the patient is about 9 months old to about 11 years old.

[0027] As used herein, “treatment,” “treating,” and “treat” are defïned as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development ofthe condition, and/or (c) relieving the condition, i.e., causing régression of the condition and/or relieving one or more symptoms of the condition. For purposes of treatment of sickle cell disease, bénéficiai or desired clinical results include, but are not limited to, multi-lineage hématologie improvement, decrease in the number of required blood transfusions, decrease in infections, decreased bleeding, and the lîke. For purposes of treatment of interstitial pulmonary fibrosis, bénéficiai or desired clinical results include, but are not limited to, réduction in hypoxia, réduction in fibrosis, and the like.

[0028] As used herein, “% w/w” refers to the weight of a component based on the total weight of a composition comprising the component. For instance, if component 1 is present in an amount of 50% in a 100 mg composition, component 1 is present in an amount of 50 mg. In some embodiments, the composition refers to a tablet as described herein.

Voxelotor

[0029] Voxelotor is a small molécule allosteric modifier of hemoglobin-oxygen affïnity in clinical development stage for the treatment of sickle cell disease (SCD). Voxelotor increases hemoglobin’s affïnity for oxygen, thereby stabilizing hemoglobin in the oxyhemoglobin State, which leads to inhibition of polymerization of sickle hemoglobin. The Chemical name for

voxelotor is 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde.

Voxelotor has the structure as shown in the following;

[0030| The synthesis of voxelotor is described in U.S. Patent No. 9,018,210 and U.S. Patent 5 No. 10,077,249, the disclosures of each of which are incorporated herein by reference in their entireties.

[0031 ] The crystalline solid form of voxelotor includes, for example, crystalline Form 1, Form II or Form N as disclosed in PCT Application Publication No. WO 2015/120133, the disclosure of which is incorporated herein by reference in its entirety.

[0032] In some embodiments, voxelotor ts an ansolvate crystalline form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Ka radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°20 (each ±0.2 °2θ). In some embodiments, voxelotor is an ansolvate crystalline form characterized by X-ray powder diffraction peaks (Cu Ka radiation) at 13.37°, 14.37°, 19.95° and 23.92°20 (each ±0.2 °2θ). This form can hereinafter also be referred to as

Form II.

[0033] In some embodiments, voxelotor is an ansolvate crystalline form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Ka radiation) selected from 11.65°, 11.85°, 12.08°, 16.70°, 19.65° and 23.48 °20 (each ±0.2 °2θ). In some embodiments, voxelotor is an ansolvate crystalline form characterized by X-ray powder diffraction peaks (Cu Ka radiation) at 11.65°, 11.85°, 12.08°, 16.70°, 19.65° and 23.48 °2θ (each ±0.2 °2θ). This form can hereinafter also be referred to as Form N or Material N.

[0034] In some embodiments, voxelotor is an ansolvate crystalline form characterized by at least two, three or four X-ray powder diffraction peaks (Cu Ka radiation) selected from 12.82°,15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82, and 26.44° °20 (each ±0.2 °20). In some 25 embodiments, voxelotor is an ansolvate crystalline form characterized by X-ray powder

diffraction peaks (Cu Ka radiation) at 12.82°, 15.74°, 16.03°, 16.63°, 17.60°, 25.14°, 25.82, and 26.44 °20 (each ±0.2 °20). This form can hereinafter also be referred to as Form I.

Hepatic Impairment

[0035] As used herein, a subject with “hepatic impairment” is a subject with a reduced 5 hepatic fonction, for example a subject diagnosed with a clinical decrease in liver fonction. The reduced liver fonction can be caused by a liver disease suffered by the subject, for example hepatic encephalopathy, hepatttîs, or cirrhosis. Sometimes, hepatic impairment can lead to liver failure. A number of methods hâve been developed to quantify hepatic fonctions and to déterminé the extent of hepatic impairment in patients, including a model end stage liver disease 10 (MELD) score and a Child-Pugh score.

[0036] The Child-Pugh score (also known as the Child-Turcotte-Pugh score) is the most commonly used method to assess the prognosis of chronic liver disease, for example cirrhosis. It is an aggregate score of five clinical measures of liver disease: total bilirubin, sérum albumin, prothrombin time prolongation or international normal ized ratio (INR), ascites, and hepatic 15 encephalopathy. Each marker is assigned a value from 1-3 points, with 3 indicating the most severe dérangement. The total value of points is used to provide a score categorized as A (5-6 points), B (7-9 points), or C (10-15 points), which can be correlated with one and two year survival rates. Category A (i.e. Child-Pugh A score of 5-6 points) is considered as mild hepatic impairment, category B is considered to be moderate hepatic impairment (i.e. Child-Pugh B 20 score of 7-9 points), and category C is considered to be severe hepatic impairment (i.e. ChildPugh B score of 10-15 points). Methods for détermination and analysis of Child-Pugh scores are well known in the art. Another commonly used scorîng System to assess hepatic impairment, the Model for End-stage Liver Disease (MELD) was initially created to predict survival among patients undergoing transjugular intrahepatic portosystemic shunt (T1PS) placement. The MELD 25 contaîns three objective variables: international normalized ratio (INR), créatinine, and total bilirubin. More recent but not unifonniy adopted modification includes addition of sodium values.

[0037] As disclosed herein, any methods recognized in the art suitable to détermine the severity of hepatic impairment of a subject can be used. In some embodiments, the hepatic 30 impairment of the patient is determined by the Child-Pugh score. The patient, for example, can

hâve a Child-Pugh score of, or about, 7, 8, 9, 10, 11, 12, 13, 14, 15, or a range between any two of these values, points. In some embodiments, the patient has a Child-Pugh score of, or about, 10, 11, 12, 13, 14, 15, or a range between any two of these values, points. In some embodiments, the patient has a Child-Pugh score of 10-15 points (i.e. category C).

[0038] Hepatic impairments tn the patients can be caused by various conditions and reasons including, but not limited to liver diseases, cancers, autoimmune diseases, toxins, metabolic diseases, shock (e.g., sepsis, hepatic shock), vascular diseases (e.g., Budd-Chiari syndrome), hypoxemia, médication uses or overuses, and any combinations thereof. For example, the hepatic impairment of the patient can be caused by a liver disease, for example a chronic liver disease or an acute liver disease. The liver diseases can be caused by, for example, infections (e.g., parasite and/or viral infections), immune System abnormality, genetic abnormality, cancer and other growths, chronic alcohol abuse, and/or accumulation of fat in the liver. Examples of liver diseases include, but are not limited to, hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E), autoimmune hepatitis, alcoholic hepatitis, primary biliary cirrhosis, primary scierosing cholangitis, hemochromatosis, hyperoxaluria and oxalosis, Wilson’s disease, alpha-1 antitrypsin défieiency, liver cancer, bile duct cancer, liver adenoma, fatty liver disease (including alcoholic fatty liver disease and nonalcoholic fatty liver disease), cirrhosis, hypoperfusion, or any combination thereof. In some embodiments, the hepatic impairment of the patient is caused by a physical injury to the liver. In some embodiments, the hepatic impairment of the patient is caused by liver inflammation. In some embodiments, the hepatic impairment of the patient is caused by the use or excess use of one or more drugs, for example acetaminophen, narcotic-acetaminophen combination médications, statin type of drugs for controlling elevated blood levels of cholestérol, niacin, antibiotics (e.g., nitrofurantoin, amoxicillin and clavulanic acid, tetracyciine, and isoniazid), drugs for treating autoimmune disorders and/or cancers (e.g., methotrexate), drugs for treating alcoholics (e.g., disulfiram), or any combination thereof. In some embodiments, the hepatic impairment of the patient is caused by a use or an excess use of one or more herbal suppléments, including but not limited to, kava, ephedra, skullcap and pennyroyal. In some embodiments, the hepatic impairment of the patient is caused by an excess use of vitamins (e.g., vitamin A). In some embodiments, the hepatic impairment of the patient is caused by food (e.g., mushrooms).

[0039] The chronic liver disease can be, for example, liver fïbrosis, cirrhosis, end-stage liver disease (ESLD), hepatocellular carcinoma, hepatic steatosis (i.e., fat in the liver), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), portai hypertension, or any combination thereof. In some embodiments, the hepatic impairment is caused by chronic liver injury. In some embodiments, the hepatic impairment is caused by hepatic inflammation. Some patients can hâve ascites, bleeding diathesis, varîceal bleeding, hepatic inflammation, rénal dysfunction, hepatic encephalopathy, increased susceptibility to infection, and multi-organ dysfonction. The cirrhosis can be compensated or decompensated. In some embodiments, the patient having severe hepatic impairment suffers from a chronic hepatic disease. In some embodiments, the patient having severe hepatic impairment suffers from a chronic hepatic injury.

[0040] In some embodiments, the method further comprises identifying a patient having sickle cell disease that also has severe hepatic impairment. For example, clinical data or test results from a patient can be used to déterminé if a patient has sickle cell disease and severe hepatic impairment. In some embodiments, the identification can be made by a medical professional by using information obtained from the patient, information obtained from the patient’s medical records, or information collected from test results. A medical professional having this information avaîlable to them and being able to identity subjects having sickle cell disease and severe hepatic impairment can practice the methods disclosed herein.

Methods of Treatment for Patients with Hepatic Impairment

[0041] Whether dose adjustment is needed in patients with hepatic impairment can be diffïcult to predict. Further, the amount of dose adjustment needed is also difficult to predict, including for mild, moderate, or severe hepatic impairment patients.

[0042] It is contemplated that the dose of voxelotor for patients with normal liver fonction may need to be adjusted for patients with hepatic impairment. Disclosed herein include methods 25 for using voxelotor for the treatment of sickle cell disease in patients also having hepatic impairment, for example severe hepatic impairment.

[0043] In some embodiments, the patient suffers from sickle cell disease and liver disease. In some embodiments, the patient has sickle cell disease and severe hepatic impairment. In some embodiments, the patient has sickle celï disease and moderate hepatic impairment. In some embodiments, the patient has sickle cell disease and mild hepatic impairment.

[0044] In some embodiments, the patient can also be a patient suffering from sickle cell disease and a condition that can cause a severe hepatic impairment as described herein. For example, the condition can be cancer, liver injury, autoimmune disease, drug overuse, or any combination thereof. The patient’s âge can vary. For example, the patient can be an adult, a child or juvénile. In some embodiments, the patient is at least 18 years old. In some embodiments, the patient is about 9 months old to about 11 years old.

[0045] In some embodiments, the methods described herein comprise administering to the patient a therapeutically effective amount of voxelotor. The administration can be oral administration, for example in the form of capsules or tablets. The administration car) be, for example, once daily, twice or three times a day, or once two days. In some embodiments, the administration is once daily. In some embodiments, the methods comprise administering to the patient one or two tablets described herein comprising a therapeutically effective amount of voxelotor per day.

[0046] In some embodiments, the dose of voxelotor is reduced to avoid a treatment-emergent adverse event. In some embodiments, the treatment-emergent adverse event is diarrhea. In some embodiments, the treatment-emergent adverse event is a headache. In some embodiments, the treatment-emergent adverse event is nausea, arthralgia, an upper respiratory tract infection, abdominal pain, fatigue, rash, pyrexia, pain in extremity, back pain, vomiting, pain, noncardiac chest pain, or upper abdominal pain. In some embodiments, the treatment-emergent adverse event is abdominal pain, diarrhea, nausea, fatigue, or pain. In some embodiments, the treatmentemergent adverse event is diarrhea, abdominal pain, nausea, fatigue, rash, or drug hypersensitivity.

[0047] In some embodiments, the method comprises administering to the patient one to three tablets described herein, wherein each of the one to three tablets comprises about 500 mg of voxelotor and wherein the administration is I to 3 times daily. In some embodiments, the method comprises administering to the patient two tablets described herein once daily, wherein each of the two tablets comprises about 500 mg of voxelotor.

[0048] In some embodiments, the methods comprise administering to the patient 500 mg to I000 mg of voxelotor per day. In some embodiments, the methods comprise administering to the patient 500 mg of voxelotor per day. In some embodiments, the methods comprise administering to the patient 1000 mg of voxelotor per day. In some embodiments, the methods comprise administering to the patient one tablet of voxelotor per day, wherein the tablet comprises 500 mg voxelotor. In some embodiments, the methods comprise administering to the patient two tablets of voxelotor per day, wherein each of the two tablets comprises 500 mg voxelotor. In some embodiments, the methods comprise administering to the patient two tablets of voxelotor at once per day, wherein each of the two tablets comprises 500 mg voxelotor. In some embodiments, the 10 methods comprise administering to the patient in a single oral dose of two tablets of voxelotor daily, wherein each of the two tablets comprises 500 mg voxelotor.

[0049] Some embodiments provide for methods of treating sickle cell disease in a patient in need thereof, comprising administering to the patient 1000 mg of voxelotor once daily, wherein the patient has severe hepatic impairment.

[0050] Some embodiments provide for methods of treating sickle cell disease in a patient in need thereof, comprising administering to the patient 1500 mg of voxelotor once daily, wherein the patient has mild or moderate hepatic impairment.

[0051] Duration of the treatment can vary. For example, voxelotor can be administered to the patient for at least about, or for about, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 20 35, 36, or a range between any two of these values, days.

[0052] In some embodiments, voxelotor (e.g., the tablet(s) of voxelotor) is administrated to the patient with food. In some embodiments, voxelotor (e.g., the tablet of voxelotor) is administrated to the patient without food.

Methods of Treatment to Avoid Drug-Drug Interactions (“DDI”)

[0053] The cytochrome P450 (CYP) is a superfamily of enzymes responsible for the metabolic transformation of drugs, with CYP3A4 being the most prévalent CYP enzyme in the liver. CYP3A4 activîty can be induced (or accelerated) or inhibited (decreased), which can impact drug concentrations. The inhibition of CYP3A4 can resuit in the accumulation of parent drug concentrations that can put the patient at increased risk for side effects and possible toxicity.

[0054] It has been found that voxelotor is a moderate inhibîtor of CYP3A4 in humans, which may resuit in increased exposures of CYP3A4 substrates. Accordingly, provided herein are methods for administering voxelotor and avoiding or lessening potential drug-drug interactions.

[0055] A “strong inhibîtor” of a CYP enzyme as used herein is an inhibîtor that caused a greater than 5-fold increase in the plasma AUC values or more than 80% decrease in clearance of CYP substrates (not I im ited to sensitive CYP substrate) in c ! in ical évaluations.

[0056] A “moderate inhibîtor” is an inhibîtor that caused a less than 2-foki but greater than 5-fold increase in the AUC values or 50-80% decrease in clearance of sensitive CYP substrates when the inhibîtor was given at the highest approved dose and the shortest dosing interval in 10 clinical évaluations.

[0057] As used herein, a “sensitive CYP3A4 substrate” or “sensitive CYP3A4 substrate with a narrow therapeutic index” refers to a modulator of CYP3A4 where small différences in dose or blood concentration of the modulator may lead to dose and blood concentration dépendent, serious therapeutic failures or adverse drug reactions. Non-limîting examples of a sensitive

CYP3A4 substrate with a narrow therapeutic index include, but are not limited to, aminophylline, cyciobenzaprine, meperidine, temosirolimus, buspirone, rîlpivirine, tadalafil, and dasatinib. In some embodiments, the sensitive CYP3A4 substrate with a narrow therapeutic index is alfentanil, cyclosporine, fentanyl, quinîdine, sirolimus, or tacrolimus.

[0058] Non-limiting examples of a strong CYP3A4 inhibîtor include, but are not limited to,

VIEK.IRA PAK(ombitasavir, partiaprevir, rîtonavir and dasabuvir), indinavir/ritonavir, tipranavir, rîtonavir, cobicistat, kétoconazole, indinavir, troleandomycin, telaprevir, danoprevir, elvitegravir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, voriconazole, mifepristone, mibefradil, LCL161, clarithromycin, posaconazole, telithromycin, grapefruit juice, ceritinib, conivapatan, nefazodone, nelfinavir, saquinavir, ribociclib, idelisib, boceprevir, and atazanavir.

[0059] Non-limiting examples of a strong CYP3A4 inducers include, but are not limited to, rifampin, mitotane, avasimibe, rifapentine, apalutamide, ivosidenib, phenytoin, carbamazpeine, enzalutamide, St. John’s Wort extract, lumacaftor, and phénobarbital.

[0060] Non-limiting examples of a moderate CYP3A4 înducers are ritonavîr and St. John’s wort. semagacestat, efavirenz, tipranavir and ritonavîr, dabrafenib, lesinurad, bosentan, genistein, thioridazine, rifabutin, lorlatinib, nafcillin, lopinavir, daclatasvir and asunaprevir and beclabuvir, modafînil, PF-06282999, etravirine, elagolix, lersirvine, and teleotristat ethyl.

[0061] In some embodiments, voxelotor is not an inhibitor of P-glycoprotein (“P-gp”).

[0062] In some embodiments, voxelotor is not an inhibitor of CYPIA2, CYP2C9, CYP2C19,

CYP2C8, or CYP2D6. In such embodiments, a patient is administered about 1500 mg of voxelotor per day.

[0063] Some embodiments provide for a method of treating sickle cell disease in a patient in 10 need thereof, comprisîng administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and avoiding co-administration of a strong CYP3A4 inhibitor.

[0064] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprisîng administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and avoiding co-administration of fluconazole.

[0065] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprisîng administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and avoiding co-administration of a moderate or a strong CYP3A4 inducer.

[0066] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprisîng administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and avoiding co-administration of a sensitive CYP3 A4 substrate with a narrow therapeutic index.

[0067] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprisîng administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and instructing the patient to avoid co-administration of a strong CYP3A4 25 inhibitor.

[0068] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprisîng administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and instructing the patient to avoid co-administration of fluconazole.

[0069] Some embodîments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about ] 500 mg of voxelotor per day, and instructing the patient to avoid co-administration of a moderate or a strong CYP3A4 inducer.

[0070] Some embodîments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and instructing the patient to avoid co-administration of a sensitive CYP3A4 substrate with a narrow therapeutic index.

[0071] Some embodîments provide for a method of treating sickle cell disease in a patient in 10 need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, wherein the patient is not administered a strong CYP3A4 inhibitor.

[0072] Some embodîments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, wherein the patient is not administered fluconazole.

[0073] Some embodîments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, wherein the patient ts not administered a moderate or a strong CYP3A4 inducer.

[0074] Some embodîments provide for a method of treating sickle cell disease in a patient in 20 need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein the patient is not administered a sensitive CYP3A4 substrate with a narrow therapeutic index.

[0075] Some embodîments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein the patient is not co-administered a strong CYP3A4 inhibitor.

[0076] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein the patient is not co-administered fluconazole.

[0077] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein the patient is not co-administered a moderate or a strong CYP3A4 inducer.

[0078] Some embodiments provide for a method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein the patient is not co-administered a sensitive CYP3A4 substrate with a narrow therapeutic index.

[0079] In some embodiments, the patient is administered about 1500 mg of voxelotor per 10 day.

[0080] In some embodiments, the sensitive CYP3A4 substrate with a narrow therapeutic index is midazolam, alfentanil, cyclosporine, fentanyl, quinidine, sirolimus, and tacrolimus.

[0081] Some embodiments provide for a method of administering voxelotor to a patient in need thereof, comprising first discontinuing administration of a strong CYP3A4 inhibitor to 15 avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutîcally effective amount of voxelotor, wherein the patient bas sickle cell disease.

[0082] Some embodiments provide for a method of administering voxelotor to a patient in need thereof, comprising first discontinuing administration of fluconazole to avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutîcally effective 20 amount of voxelotor, wherein the patient has sickle cell disease.

[0083] Some embodiments provide for a method of administering voxelotor to a patient in need thereof, comprising first discontinuing administration of a moderate or strong CYP3A4 inducer to avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutîcally effective amount of voxelotor, wherein the patient has sickle cell disease.

[0084] In some embodiments, the methods comprise first discontinuing administration of a moderate CYP3A4 inducer. In some embodiments, the methods comprise first discontinuing administration of a strong CYP3A4 inducer.

[0085] Some embodiments provide for a method of administering voxelotor to a patient in need thereof, comprising first discontinuing administration of a sensitive CYP3A4 substrate with a narrow therapeutîc index to avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutically effective amount of voxelotor, wherein the patient has sickle cell disease.

[0086] In some embodiments, the therapeutically effective amount of voxelotor is about 500 5 mg to about 1500 mg per day.

[0087] In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued concurrently with starting administration of voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued 1, 2, or 3 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between 1 day to 7 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between 1 day to 14 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between I day to 21 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between 1 day to 1 month prior to starting administration with voxelotor.

[0088] In some embodiments, administration of fluconazole is discontinued concurrently with starting administration of voxelotor. In some embodiments, administration of fluconazole is discontinued 1, 2, or 3 days prior to starting administration with voxelotor. In some embodiments, administration of a fluconazole is discontinued between 1 day to 7 days prior to starting administration with voxelotor. In some embodiments, administration of fluconazole is discontinued between 1 day to 14 days prior to starting administration with voxelotor. In some embodiments, administration of fluconazole is discontinued between 1 day to 21 days prior to starting administration with voxelotor. In some embodiments, administration of fluconazole is discontinued between 1 day to 1 month prior to starting administration with voxelotor.

[0089] In some embodiments, administration of a moderate CYP3A4 inducer is discontinued concurrently with starting administration of voxelotor. In some embodiments, administration of a moderate CYP3A4 inducer is discontinued 1, 2, or 3 days prior to starting administration with voxelotor. In some embodiments, administration of a moderate CYP3A4 inducer is discontinued between 1 day to 7 days prior to starting administration with voxelotor. In some embodiments, administration of a moderate CYP3A4 inducer is discontinued between 1 day to 14 days prior to

starting administration with voxelotor. In some embodiments, administration ofamoderate CYP3A4 inducer is discontinued between l day to 2I days prior to starting administration with voxelotor. In some embodiments, administration of a moderate CYP3A4 inducer is discontinued between l day to l month prior to starting administration with voxelotor.

[0090] In some embodiments, administration of a strong CYP3 A4 inhibitor is discontinued concurrently with starting administration of voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued l, 2, or 3 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between l day to 7 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between 1 day to 14 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between 1 day to 21 days prior to starting administration with voxelotor. In some embodiments, administration of a strong CYP3A4 inhibitor is discontinued between 1 day to 1 month prior to starting administration with voxelotor.

[0091] In some embodiments, administration of a sensitive CYP3A4 substrate with a narrow therapeutic index is discontinued concurrently with starting administration of voxelotor. In some embodiments, administration of a sensitive CYP3A4 substrate with a narrow therapeutic index is discontinued 1, 2, or 3 days prior to starting administration with voxelotor. In some embodiments, administration of a sensitive CYP3A4 substrate with a narrow' therapeutic index is discontinued between 1 day to 7 days prior to starting administration with voxelotor. In some embodiments, administration of a sensitive CYP3A4 substrate with a narrow therapeutic index is discontinued between 1 day to 14 days prior to starting administration with voxelotor. In some embodiments, administration of a sensitive CYP3A4 substrate with a narrow therapeutic index is discontinued between 1 day to 21 days prior to starting administration with voxelotor. In some embodiments, administration of a sensitive CYP3A4 substrate with a narrow therapeutic index is discontinued between 1 day to 1 month prior to starting administration with voxelotor.

[0092] In some embodiments. a method of concurrently administering voxelotor and a sensitive CYP3A4 substrate with a narrow therapeutic index comprises administering to a patient a therapeutically effective amount of voxelotor and a dosage of a sensitive CYP3A4 substrate

with a narrow therapeutic index that is decreased relative to a patient taking a sensitive CYP3A4 substrate with a narrow therapeutic index.

[0093] In some embodiments, a method of concurrently administering voxelotor and a strong or moderate CYP3A4 inducer comprises administering to a patient a therapeutically effective 5 amount of a strong or moderate CYP3A4 inducer and a dosage of voxelotor thaï is increased relative to a patient not taking a strong or moderate CYP3A4 inducer.

[0094] In some embodiments, the dosage of voxelotor that is increased is 2,500 mg per day.

[0095] In some embodiments, a method of concurrently administering voxelotor and fluconazole or a strong CYP3A4 inhibitor comprises administering to a patient a therapeutically 10 effective amount of fluconazole or a strong CYP3A4 inhibîtor and a dosage of voxelotor that is decreased relative to a patient not taking fluconazole or a strong CYP3A4 inhibitor.

[0096| In some embodiments, the dose of voxelotor that is decreased is about 1,000 mg per day. In some embodiments, the dose of voxelotor that is decreased is about 500 mg per day.

[0097] In some embodiments. the patient is already being administered a sensitive CYP3A4 15 substrate with a narrow therapeutic index, moderate CYP3A4 inducer, strong CYP3A4 inducer, fluconazole, or strong CYP3A4 inhibitor. In some embodiments, the patient is already being administered voxelotor.

[0098] In some embodiments, the dosage of voxelotor is increased prior to administration of a moderate or strong CYP3A4 inducer.

[0099] In some embodiments. the dosage of voxelotor is decreased prior to administration of a strong CYP3A4 inhibitor or fluconazole.

[0100] Also provided herein are methods of administering voxelotor to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of voxelotor, and advising the patient one or more of the followîng:

(a) advising the patient that a sensitive CYP3A4 substrate with a narrow therapeutic index, moderate CYP3A4 inducer, strong CYP3A4 inducer, fluconazole, or strong CYP3A4 inhibitor should be avoided or discontinued;

(b) advising the patient that co-administration of voxelotor with a sensitive CYP3A4 substrate with a narrow therapeutic index, moderate CYP3A4 inducer, strong CYP3A4 inducer, fluconazole, or strong CYP3A4 inhibitor can alter the therapeutic effect of voxelotor;

(c) advising the patient that co-administration of voxelotor and a moderate CYP3A4 inducer or strong CYP3A4 inducer can decrease voxelotor plasma concentrations and may lead to reduced efficacy;

(d) advising the patient that co-administration of voxelotor and a strong CYP3A4 inhibitor can increase voxelotor plasma concentrations and may lead to increased toxîcity;

(e) advising the patient that co-administration of voxelotor with a sensitive CYP3A4 substrate with a narrow therapeutic index can increase the systemic exposure of the sensitive CYP3A4 substrate with a narrow therapeutic index;

(f) advising the patient to replace a strong CYP3A4 inhibitor or fluconazole with an alternative drug;

(g) if co-administration of a strong CYP3A4 inhibitor or fluconazole is unavoidable, 15 decreasing the dose of voxelotor to i 000 mg per day;

(h) if co-administration of a moderate CYP3A4 inducer or strong CYP3A4 inducer is unavoidable, increasing the dose of voxelotor to 2500 mg per day;

(i) if co-administration of a sensitive CYP3A4 substrate with a narrow therapeutic index is unavoidable, decreasing the dose of the sensitive CYP3A4 substrate with a narrow therapeutic 20 index.

Dosage Forms of Voxelotor

[0101] Voxelotor may be administered in any suitable dosage form, including an oral dosage form.

[0102] In some embodiments, voxelotor îs administered as a capsule. Capsules of voxelotor 25 are described in U.S. Patent Publication No. 2017/0157101, which is hereby incorporated by reference in its entirety.

[0103] In some embodiments, voxelotor is administered as a tablet. Tablets and dispersible tablets of voxelotor are described in U.S. Patent Publication No. US 2018/0125789, which is hereby incorporated by reference in its entirety.

[0104] In some embodiments, the tablets described herein comprise voxelotor as a substantially pure crystalline ansolvate form characterized by at least two X-ray powder diffraction peaks (Cu Ka radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°20 (each ±0.2 °20). In some embodiments, the tablets described herein consists essentially of voxelotor as a crystalline ansolvate form characterized by at least two X-ray powder diffraction peaks (Cu Ka radiation) selected from 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2 °20). In some embodiments, the tablets described herein comprise a crystalline ansolvate form of voxelotor characterized by X-ray powder diffraction peaks (Cu K a radiation) at 13.37°, 14.37°, 19.95° and 23.92°2θ (each ±0.2 °2θ).

[0105] The tablets described herein comprise voxelotor (e.g., Form I, Form II, or Form N) at an amount of, or at an amount of about, 55%, 56%, 57%, 58%, 59.1%, 59.2%, 59.3%, 59.4%, 15 59.5%, 59.6%, 59.7%, 59.8%, 59.9%, 60%, 61%, 62%, 63%, 64%, 65% w/w, or a range between any two of these values, wherein the percentage by weight is relative to the total weight of the tablet. In some embodiments, the tablet comprises, or comprises about, 50% to about 70% w/w of voxelotor (e.g., Form II). In some embodiments, the tablet comprises, or comprises about 60% w/w of voxelotor (e.g., Form II).

[0106] The tablets described herein comprise about 300 mg to about 1500 mg or about 300 mg to about 900 mg of voxelotor (e.g., Form 1, Form II, or Form N). The tablets described herein comprise about 100 mg to about 600 mg of voxelotor (e.g., Form I, Form II, or Form N). In some embodiments, the tablets described herein comprise voxelotor (e.g., Form I, Form II, or Form N) in an amount of, or in an amount of about 500 mg.

[0107] The tablets disclosed herein comprise excipients such as a pharmaceutically acceptable filler (also known as diluent), désintégrant, lubricant, surfactant (also known as wetting agent), glidant, and binder.

|0108] In some embodiments, the tablets described herein comprise microcrystalline cellulose (MCC). In some embodiments, the MCC is présent in the tablet at, or at about, 30%,

31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or a range between any two of these values, w/w. In some embodiments, the MCC is present in the tablet at about 30% to about 40% w/w. In some embodiments, the MCC is present in the tablet at, or at about, 35% w/w.

[0109] The tablets described herein comprise, in some embodiments, one or more disintegrants. Suitable disintegrants include, either individually or in combination, starches including pregelatinized starch and sodium starch glycolate; clays; magnésium aluminum silicate; cellulose-based disintegrants such as powdered cellulose, microcrystalline cellulose, methylcellulose, low-substituted hydroxypropylcellulose, carmellose, carmeHose calcium, carmellose sodium and croscarmellose sodium; alginates; povidone; crospovidone; polacrilin potassium; gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums; colloïdal Silicon dioxide; and the like.

[0110] In some embodiments, the disintegrant is croscarmellose sodium. The tablets comprise, or comprise about, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5% 1.6%, 1.7%, 1.8%, 1.9%, or 2% or a range between any two of these values, w/w of one or more disintegrants. In some embodiments, the tablets comprise about 0.25% to about 3% w/w of a disintegrant. In some embodiments, the tablets comprise about 0.25% to about 3% w/w of croscarmellose sodium. In some embodiments, the tablets comprise about 1.25% w/w of croscarmellose sodium.

[OUI] The tablets described herein comprise one or more surfactants (also known as wetting 20 agents). In some embodiments, the tablets comprise sodium lauryl sulfate as a surfactant. In some embodiments, the surfactant can be present in the tablets disclosed herein at an amount of, or at an amount of about, 0.1%, 0.5%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.9%, 2.0%, 2.5%, 3%, 4%, 5%, or a range between any two of these values, w/w. In some embodiments, the tablets do not comprises a surfactant. In some embodiments, the tablets comprise about 0.5% to about 2.5% w/w of sodium lauryl sulfate. In some embodiments, the tablets comprise sodium lauryl sulfate at an amount of about 1.5% w/w.

[0112] The tablets described herein comprise one or more lubricants. Exemplair lubricants include, either individually or in combination, glyceryl behenate; stearic acid and salts thereof, including magnésium, calcium and sodium stéarates; hydrogenated vegetable oils; glyceryl

palmitostearate; talc; waxes; sodium benzoate; sodium acetate; sodium fumarate; sodium stearyl fumarate; PEGs (e.g., PEG 4000 and PEG 6000); poioxamers; polyvinyl alcohol; sodium oleate; sodium lauryl sulfate; magnésium lauryl sulfate; and the like. In some embodiments, the lubricant can be présent in the tabiets at an amount of, or at an amount of about, 0.25%, 0.5%,

0.75%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.5%, 2.75%, 3%, 4%, 5%, or a range between any two of these values, w/w. In some embodiments, the lubricant is magnésium stéarate. In some embodiments, magnésium stéarate is présent in the tabiets in the amount of from about 1% to about 5% w/w. In some embodiments, magnésium stéarate is présent in the tabiets in the amount of about 2% w/w.

[0113] The tabiets described herein comprise one or more binders. Exemplary binding agents and adhesives include, acacia; tragacanth; glucose; polydextrose; starch including pregelatinized starch; gelatin; modified celluloses including methylcellulose, cannellose sodium, hydroxypropylmethylcellulose (HPMC or hypromellose), hydroxypropyl-cellulose, hydroxyethylcellulose and ethylcellulose; dextrins including maltodextrin; zein; alginic acid and salts of alginic acid, for example sodium alginate; magnésium aluminum silicate; bentonite; polyethylene glycol (PEG); polyethylene oxide; guar gum; polysaccharide acids; and the like.

[0114] The tabiets described herein comprise one or more glidants. Exemplary glidants include, colloïdal Silicon dioxide, starch, powdered cellulose, sodium lauryl sulfate, magnésium trisilicate and metallic stéarates. In some embodiments, the glidant is colloïdal Silicon dioxide. In 20 some embodiments, the tablet comprises about 0.1% to about 5% by weight of colloïdal Silicon.

In some embodiments, the tablet comprises about 0.5% to about 1% by weight of colloïdal Silicon dioxide. In some embodiments, the tablet comprises about 0.75% by weight of colloïdal Silicon dioxide.

[0115] Other excipients such as colorants (coloring agents), coating polymers, flavors (flavoring agents), and sweeteners are known in the pharmaceutical art and can be used in the tabiets disclosed herein. Non-limiting examples of a sweetener are sucrose, xylitol, maltitol, mannitol, sorbitol, sucralose, sodium saccharin, acesulfame potassium, aspartame, and others known to those of skill in the art. In some embodiments, the coloring agent is iron oxide yellow.

[0116] In some embodîments, a tablet comprises about 50% to about 70% by weight voxelotor; about 30% to about 40% by weight of microcrystalline cellulose; about 0.25% to about 3% by weight of croscarmellose sodium; about 1% to about 5% by weight of magnésium stéarate; about 0.5% to about 2.5% of sodium lauryl sulfate; and about 0.25% to about 5% by weight of colloïdal Silicon dioxide; wherein the percentage by weight is relative to the total weight of the tablet.

[0117] In some embodîments, tablets described herein include a coating surroundîng the core described herein comprising Compound 1. Tablets can be coated using formulations known in the art, such as for example, excipients such as talc, polyvînyl alcohol, and PEG (e.g., PEG 4000 and PEG 6000). In some embodîments, the coating polymer can be hydroxypropyl methylcellulose (HPMC). When coated, tablets comprise a core that is coated with a nonfunctional film or a release-modifying or enteric coating.

[0118] It is understood that modifications which do not substantially affect the activity of the various embodîments of this disclosure are also included within the définition of the disclosure provided herein. Accordingly, the following examples are intended to illustrate but not limit the present disclosure.

EXAMPLES

Example 1: Characterization of pharmacokinetics and safety of a single oral dose of voxelotor in subjects with hepatic impairment

[0119] A Phase 1, open-label study was performed to characterize pharmacokinetics (PK) and safety of a single oral dose of voxelotor in subjects with hepatic impairment. The study was to assess the effects of mild, moderate, or severe hepatic impairment on the PK of a single oral dose of voxelotor, to evaluate the safety and tolerabîlity of a single oral dose of voxelotor in subjects with mild, moderate, or severe hepatic impairment, as well as to establish potential dose adjustment guidance based upon the degree of hepatic insuffleiency.

[0120] List of Abbreviations:

AE	adverse event
BMI	body mass index

CYP	Cytochrome P450
CRU	clinical research unit
ECG	electrocardiogram
eCRF	Electronic case report form
LS	least squares
max	maximum
OTC	over-the-counter
PK	pharmacokinetic(s)
PT	preferred term
SAE	serions adverse event
TEAE	treatment-emergent adverse event

Study design

[0121] This was a Phase l, multiple-center, nonrandomized, open-label, parallel group study of a single oral dose of voxelotor administered in subjects with mild (Child-Pugh A; score 5 to 6 5 points), moderate (Child-Pugh B; score 7 to 9 points), or severe (Child-Pugh C; score 10 to 15 points) hepatic impairment and subjects with normal hepatic function. This study was designed to assess the effects of mild, moderate, or severe hepatic impairment on the PK of a single oral dose of voxelotor. Routine safety assessments (AE monitoring, vital signs, physical examinations, clinical laboratory tests, and ECGs) were performed.

[0122] Twenty-eight subjects were enrolled (a ratio of 7:7:7:7 subjects per hepatic function group: normal hepatic function, mild, moderate, or severe hepatic impairment, respectively). An additional subject was dosed in error and was discontinued from the study. The group demographics between the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups were similar (i.e., with respect to âge [i 10 years], gender, and BMI 15 [± 10%]).

[0123] The screening window was 28 days in duration.

[0124] Subjects with mild and moderate hepatic impairment were enrolled first. Once at least 4 subjects in each of these 2 groups completed the clinical portion of the study (through Day 5 PK sample), an intérim analysis was performed on voxelotor whole blood and plasma concentration data for subjects in these 2 groups comparing data to historical data in heaîthy subjects to déterminé if there was an increase in exposure and if a dose adjustment was therefore needed for subjects with severe hepatic impairment. The subjects with normal hepatic function were enrolled last, once at least 4 subjects with severe hepatic impairment were enrolled.

[0125] Subjects remained in the CRU until discharge on Day 5 and returned to the CRU on Days 12 (± I day) and 20 (± 1 day) for voxelotor whole blood and plasma PK and safety assessments. Ail subjects (including the subject who terminated the study early) returned for a follow-up visit on Day 28 (± 2 days).

|0126] Safety and PK assessments were performed at select time points throughout the study.

Treatments

[0127] Eligible subjects received a single oral dose of voxelotor 1500 mg (5 x 300-mg capsules) on Day 1 (for normal hepatic function, mild and moderate hepatic impairment). A lower dose of voxelotor 600 mg (2 x 300-mg capsules) was administered for the subjects with severe hepatic impairment. The decision to proceed with a lower dose of voxelotor in subjects with severe hepatic impairment was based on the observation of TEAE of diarrhea (mild) occurring in 5 of 7 subjects (71.4%) with moderate hepatic impairment.

[0128] Following an overnight fast of at least 10 hours voxelotor was administered with approximately 240 mL (8 fluid ounces) of nonrefrigerated, noncarbonated water. No food was allowed for at least 4 hours postdose. No water or any type of liquid was allowed for 1 hour before dosing through 1-hour postdose with the exception of water consumed for dosing.

[0129] For subjects with normal hepatic function, no concomitant médications (prescription, 25 OTC, and herbal, including any drugs that induced study drug spécifie CYPs) were administered during the study to subjects with normal hepatic function unless they were prescribed by the investigator for treatment of spécifie clinical events (î.e., AEs).

[0130] For hepatically impaired subjects, they were on a stable dose of médication and/or treatment regimen at least 2 weeks prior to study drug dosing (if applicable). Required

concomitant médications were administered at least 2 hours before or 8 hours after voxelotor dosing. No herbal médications or strong inducers/inhibitors of CYPs (2B6, 2C9, 2C19, 3A4, and 3A5), or any drug that could hâve potentially affected the absorption of voxelotor, were administered during the study. No other médication other than already stable doses that the subjects were on was administered during the study unless they were prescribed by the investigator for treatment of spécifie clinical events (i.e., AEs).

[0131] Ail médications (prescription and OTC), vitamin and minerai suppléments, and herbs taken during the study were documented on the concomitant médication eCRF. Information recorded included start and stop dates, dose and route of administration, and indication,

Médications taken for a procedure were included,

Pharmacokinetic and safety variables

[0132] Pharmacokinetic variables measured included: C_max, tmax, AUCt, AUCO-96, AUCinf, t'A, λζ, CL/F, Vz/F, F_u, AUCmfu, AUCtu, Cmax,u, and CL/Fu.

[0133] Adverse events and concomitant médication use were monitored throughout the study. Safety assessments, including physical examinations, vital signs assessments, 12-lead ECGs, and clinical laboratory tests, were performed. Whole blood and plasma concentrations of voxelotor were determined using validated assays.

[01341 Analysis populations: (1) “Pharmacokinetic Full Population” includes ail subjects who received at least one dose (1500 mg or 600 mg) of voxelotor and had at least one whole blood or plasma concentration data point. (2) “Pharmacokinetic Evaluable Population” includes ail subjects who received at least 1 dose of voxelotor and had a sufficient P K profile to dérivé at least 1 PK. parameter. (3) “Safety Population” includes ail subjects who received any amount of voxelotor.

[0135J Pharmacokinetic variables were calculated from the whole blood and plasma 25 concentrations of voxelotor using noncompartmental methods (Phoenix WinNonlin®, Version

6.3. 0395, Pharsight Corp, St. Louis, MO) and actual sampling times. The following PK parameters were determined.

AUCo-96	Area under the concentration-time curve from time 0 to 96 hours; calculated using the linear/log trapezoîd rule
AUCinf	Area under the concentration-time curve from time 0 extrapolated to infinity; calculated as AUCt + CAZ, where Ct was the last quantifiable concentration and λζ was the terminal élimination rate constant determined by the slope of the terminal phase of the concentration-time curve
AUCinf,u	Unbound AUCinf for plasma
AUCt	Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration; calculated using the linear/log trapezoid rule
AUCtu	Unbound AUCt for plasma
CL/F	Apparent oral clearance
CL/F.u	Unbound CL/F for plasma
Cmax	Maximum observed concentration
Cmax.u	Unbound Cmax for plasma
Fu	Fraction of drug unbound in plasma
λζ	Terminal élimination rate constant
H	Terminal élimination half-life; calculated as ίη(2)/λζ
tmax	The time that Cmax was observed
Vz/F	Apparent volume of distribution during the terminal phase

Statistical analysis for pharmacokinetic data and safety data

[0136] Only data points that described the terminal élimination log-linear décliné were used în the régression équation for calculation of λ_ζ; C_max and any data point in the distribution phase 5 were not included in the calculation. A minimum of 3 points was used for détermination of λζ. A general rule of R² > 0.80 was considered acceptable for calculation of λζ. If R2 fell below 0.80, then λ_ζ was reported as ND and that subject’s λ_ζ, ti/2, and AUCmfwere reported as ND in the appropriate listings. If the extrapolated AUCinf was more than 20%, then AUCinf was listed but excluded from descriptive summaries and statistical analysis.

[0137] The PK full population was used for ail listings. The évaluable PK population was used for summary statistics and statistical analyses. The individual and mean whole blood and plasma drug concentrations of voxelotor versus time curves were presented for subjects. Summary statistics (n, mean, SD, minimum, maximum, and coefficient of variation) were 5 calculated for whole blood drug concentrations and plasma drug concentrations for each time point for voxelotor.

[0138] Whole blood and plasma PK parameters were listed for voxelotor. Ail PK parameters (primary and secondary) were listed. Summary statistics (n, mean, SD, géométrie mean, médian, minimum, maximum, and coefficient of variation) were calculated for the whole blood and plasma voxelotor PK parameters. For t_max, only n, minimum, médian and maximum were reported.

[0139] To assess the effect of hepatic impairment on the PK of voxelotor, a linear mixedeffect model was fitted to the log-transformed values of whole blood and plasma C_max, AUCt, and AUCmf. The model included hepatic impairment group as a fixed effect and âge and weight 15 as covariates. Point estimâtes and 90% CIs for hepatic fonction group différences (mild, moderate, and severe hepatically-impaired subjects [test] versus the normal hepatic fonction subjects [control]) on the log scale were exponentiated to obtain estimâtes for GM ratios on the original scale.

[0140] The individual treatment ratio (hepatic versus normal) for the primaiy PK parameters 20 (Cmax, AUCt, and AUCint) aîong with géométrie mean ratio and 90% CI wire displayed.

[0141] AH statistical analyses were performed using the safety population. Ail AEs were coded to SOC and PT using MedDRA (Version 19.0) and presented by subject in data listings. A treatment-emergent AE was defined as an AE that was not présent prior to treatment with study drug, but appeared following treatment or was présent at treatment initiation but worsened during 25 treatment. An AE that was présent at treatment initiation but resolved and then reappeared while the subject was on treatment was a TEAE (regardless of the intensity of the AE when the treatment was initiated). Programmatically, an AE was classified as a TEAE if the start date and time occurred on or after the start date and time of first study drug dosing. The overall incidence of TEAEs (number and percentage of subjects) as well as the number of events were summarized by hepatic fonction group, severity, SAEs, causally related TEAE and SAEs, TEAEs leading to study or treatment discontinuation, life-threatening SAEs, and SAEs resulting in death.

[0142] The TEAEs were summarized and tabulated at both the subject (number [%] of subjects) and event (number of events) level: (I) by hepatic fonction group, SOC, and PT; (2) by 5 hepatic fonction group, SOC, PT, and maximum reported severity; and (3) by hepatic fonction group, SOC, PT, and maximum relationship to study drug.

Baseline characteristics

[0143] Physical measurements were performed and the baseline physical measurements are shown in Table A.

Table A. Summary of baseline physical measurements (safety population)

Parameter	Mild (N=7)	Moderate (N=7)	Severe (N=7)	Normal (N=7)	Overall (N=28)!*
Weig	ht(kg)
Mean	83.14	90.69	82.36	86.77	85.74
SD	28.285	14.258	10.457	10.526	16.829
Médian	76.3	94.2	84.20	91.50	89.00
Minimum	61.8	66.2	67.7	69.7	61.8
Maximum	142.7	102.6	97.1	97.2	142.7
Heig	it (cm)
Mean	172.81	167.33	168.54	173.84	170.63
SD	9.738	7.096	12.578	7.505	9.371
Médian	168.8	169.00	170.00	176.50	170.00
Minimum	167.0	152.5	152.0	160.5	152.0
Maximum	194.0	174.0	185.0	180.5	194.0
Body Mass Index (kg/m2)
Mean	27.39	32.21	29.50	28.6	29.43
SD	6.226	3.329	6.374	1.656	4.898
Médian	26.40	33.00	27.00	28.20	28.65
Minimum	20.2	27.3	22.6	26.6	20.2
Maximum	37.9	36.9	38.7	31.6	38.7
a. An subject with moderate hepatic impairment was dosed in error and was discontînued from the study per sponsor request. The subject was included and listed under the Safety Population; however, has been excluded from table summaries due to the protocol déviation.

Pharmacokinetic évaluation

[0144] Voxelotor whole blood and plasma concentrations were measured using a validated liquid chromatography-mass spectrometry method. The lower limit of assay quantitation for voxelotor was I0.0 ng/mL for whole blood and 5.00 ng/mL in plasma.

[0145] Mean (+ SD) whole blood voxelotor concentration-lime profiles are presented in FIG.

1. For subjects with severe hepatic impairment, concentrations were adjusted for dose. Dose adjusted concentration = (concentration/600 mg) x 1500 mg. Overlays of whole blood voxelotor concentration-time profiles are presented in FIGS. 2A-2D with the hepatic impairments status of subjects being mild (FIG. 2A), moderate (FIG. 2B), severe (FIG. 2C), and severe with dose adjusted (FIG. 2D). For subjects with severe hepatic impairment, dose adjustment being done as they were dosed with 600 mg voxelotor compared to 1500 mg for Mild, Moderate and Normal subjects. One subject with moderate hepatic impairment had no measurable voxelotor concentrations in whole blood, but was dosed. This subject was excluded from concentration and PK summaries and statistical analysis.

[0146] As shown in FIG. 1, the mean dose adjusted whole blood concentrations were higher in subjects with severe hepatic impairment than in subjects with normal hepatic function. Subjects with mild and moderate hepatic impairment had similar voxelotor concentrations in whole blood to subjects with normal hepatic function.

[0147] Individual whole blood voxelotor PK parameters are summarized in Table B.

Statistical analyses of the effect of hepatic impairment on voxelotor whole blood PK parameters are summarized în Table C.

Table B. Summary of whole blood voxelotor pharmacokinetic parameters (pharmacokinetic évaluable population)

Parameter	Statistic	Mild	Moderate	Severea	Normal
Cmas (pg/mL)	n GM (CV%)	7 73.6 (32.8)	6 63.8 (17.4)	7 86.6 (33.6)	7 60.9 (22.4)
AUCt (h* pg/mL)	n GM (CV%)	7 8193 (29.2)	6 8324 (22.6)	7 13331 (23.3)	7 6953 (10.8)
AUCinf (h* pg/mL)	n GM (CV%)	7 8230(29.1)	6 8363 (22.8)	7 13636 (24.2)	7 6980 (10.9)

Parameter	Statistic	Mild	Modéra te	Severea	Normal
AUCo-96 (h*gg/mL)	n GM (CV%)	7 5159 (29.2)	6 4656 (15.7)	7 6052 (21.4)	7 4269(13.9)
tmax(h)	n Médian (min, max)	7 24.0 (12.0, 48.0)	6 24.0 (24.0, 24.0)	7 24.0 (24.0, 72.0)	7 24.0 (24.0, 48.0)
tl/2 (h)	n Mean (SD)	7 60.1 (60.7)	6 79.5 (18.7)	7 111 (19.1)	7 63.2(17.5)
CL/F (L/h)	n GM (CV%)	7 0.182 (32.4)	6 0.179 (23.9)	7 0.110(26.1)	7 0.215 (11.1)
Vz/F (L)	n GM (CV%)	7 15.8(31.0)	6 20.6(18.5)	7 17.6(22.0)	7 19.6(16.4)

a. For subjects with severe hepatic impairment AUC and C_max were adjusted for dose.

Dose adjusted parameter = (parameter/600 mg) χ 1500 mg.

Table C. Statistical analysis of the effect of hepatic impairment on voxelotor pharmacokinetic parameters in whole blood (pharmacokinetic évaluable population)

PK Parameter	Comparison	No. of Subjects	Géométrie LS Mean	Ratio of Géométrie LS Mean (Test to Reference)	90% CI for Géométrie LS Mean Ratio of (Test to Reference)
Test	Reference	Test	Reference
	Mild (Test) vs Normal						(0.920,
	(Ref)	7	7	72.9	61.4	1.187	1.530)
Cmax	Moderate (Test) vs Normal	6	7	64.9	61.4	1.056	(0.796,
(gg/mL)	(Ref)	7	7	85.4	61.4	1.391	1.400)
	Severe4 (Test) vs Normal				(1.080,
	(Ref)						1.790)
	Mild (Test) vs Normal						(0.922,
	(Ref)	7	7	8124	7127	1.140	1.409)
AUCt	Moderate (Test) vs Normal	6	7	8189	7127	1.149	(0.908,
(h*gg/mL)	(Ref)	7	7	13303	7127	1.867	1.454)
	Severea (Test) vs Normal					(1.512,
	(Ref)						2.304)

	Mild (Test) vs Normal						(0.920,
	(Ref)	7	7	8161	7151	1.141	1.416)
AUCinf	Moderate (Test) vs Normal	6	7	8231	7151	1.151	(0.906,
(h*pg/mL)	(Ref)	7	7	13605	7151	1.902	1.462)
	Severea (Test) vs Normal				(1.536,
	(Ref)						2.356)
The log-trans	'ormed PK parameters (Cmax, AUCt, and AUCinf) were analyzed using a	inear
mixed-effect model, with fixed effect for hepatic impairment group and âge and weight as
covariates.
a. For subjects with severe hepatic impairment, AUC and Cmax were adjusted for dose.
Dose adjusted parameter = (parameter/600 mg)	x 1500 mg.

[0148] In comparison to subjects with nonnal hepatic function, the whole blood voxelotor exposures in terrns of AUC was 14% to 15% higher in subjects with mild and moderate hepatic impairment. In comparison to subjects with normal hepatic function, the whole blood voxelotor 5 exposures in terrns of whole blood AUC adjusted for dose was 87% to 90% higher in subjects with severe hepatic impairment. In comparison to subjects with normal hepatic function, the whole blood Cnmwas 19%, 6%, and 39% higher in the mild, moderate, and severe hepatic impairment subjects, respectively (Cm_ax was adjusted for dose for the severe hepatic impairment group).

[0149] The médian t_max was similar for ail hepatic function groups. Subjects with normal hepatic function, mild, and moderate hepatic impairment had a similar mean ti/2 and CL/F. In comparison, the ti/2 was longer and the CL/F was lower tn subjects with severe hepatic impairment.

[0150] Mean (+ SD) plasma voxelotor concentration-time profiles are presented in FIG. 3. 15 For subjects with severe hepatic impairment, concentrations were adjusted for dose. Dose adjusted concentration = (concentration/600 mg) x 1500 mg. Overlays of plasma voxelotor concentration-time profiles are presented in FIGS. 4A-4D with the hepatic impairments status of subjects being mild (FIG. 4A), moderate (FIG. 4B), severe (FIG. 4C), and severe with dose adjusted (FIG. 4D). For subjects with severe hepatic impairment, dose adjustment being donc as 20 they were dosed with 600mg voxelotor compared to 1500mg for Mild, Moderate and Nonnal subjects. One subject who was dosed 1500 mg in the moderate hepatic impairment group was

excluded from concentration summaries, PK summarîes, and statistical analysis, due to not having measurable voxelotor concentrations in plasma.

[0151] As shown in FIG. 3, the mean dose adjusted plasma concentrations were higher in subjects with severe hepatic impairment than in subjects with normal hepatic fonction. Subjects 5 with mild and moderate hepatic impairment had similar voxelotor concentrations in plasma to subjects with normal hepatic fonction.

[0152] Individual plasma voxelotor PK parameters and diagnostic results are summarized in Table D. Statistical analysis of the effect of hepatic impairment on voxelotor PK parameters in plasma are summarized in Table E.

Table D. Summary of plasma voxelotor pharmacokinetic parameters (pharmacokinetic évaluable population)

		Hepatic Im	lairment Status
Parameter	Statistic	Mild	Moderate	Severe	Normal
Cmax (pg/mL)	n GM (CV%)	7 2.39 (39.1)	6 2.91 (17.9)	7 2.96 (31.1)	7 2.01 (23.3)
AUCt (h* pg/mL)	n GM (CV%)	7 223 (20.0)	6 252 (25.3)	7 386 (30.4)	7 199 (21.2)
AUCinf (h* pg/mL)	n GM (CV%)	7 224 (19.9)	5 244 (27.4)	7 393 (30.8)	7 200 (21.1)
AUCmî (h* pg/mL)	n GM (CV%)	7 143 (22.2)	6 146 (25.5)	7 177 (25.5)	7 120 (23.0)
tmax (h)	n Médian (min, max)	7 4.00 (2.00, 24.0)	6 5.00 (2.00, 48.0)	7 4.00 (2.00, 24.0)	7 4.00 (2.00, 48.0)
tl/2 (h)	n Mean (SD)	7 71.4(17.8)	5 90.0 (14.0)	7 109(16.3)	7 80.8 (13.0)
CL/F (L/h)	n GM (CV%)	7 6.69 (24.4)	5 6.14(28.7)	7 3.81 (25.5)	7 7.50(26.0)
Vz/F (L)	n GM (CV%)	7 674 (31.4)	5 789 (24.3)	7 592 (26.6)	7 865 (20.2)
Cmax Unbound (pg/mL)	n GM (CV%)	7 0.0593 (51-7)	6 0.0106 (50.4)	7 0.00622 (63.4)	7 0.00817 (29.5)
AUCt Unbound (h* pg/mL)	n GM (CV%)	7 0.503 (25.2)	6 0.919(48.2)	7 2.02 (97.4)	7 0.807 (23.1)
AUCinf Unbound (h* pg/mL)	n GM (CV%)	7 0.507 (25.1)	5 1.04 (42.6)	7 2.07 (97.9)	7 0.815 (23.1)
CL/F Unboundb (L/h)	n GM (CV%)	7 0.0151 (45.0)	5 0.0260 (24.3)	7 0.0200 (37.6)	7 0.0305 (39.1)

a. For subjects with severe hepatic impairment AUC and Cmax were adjusted for dose.

b. Resuit at 4 hours post dose.

Dose adjusted concentration = (concentration/600 mg) x 1500 mg.

Table E. Statistical Analysis of the Effect of Hepatic Impairment on Voxelotor Pharmacokinetic

Parameters in Plasma (Pharmacokinetic Evaluable Population)

		Number of Subjects	Géométrie LS Mean	Ratio of	90% CI for Géométrie
PK Paramet er	Comparison	Test	Reference	Test	Reference	LS Mean (Test to Reference)	LS Mean Ratio of (Test to Reference)
	Mild (Test) vs Normal						(0.917,
Cmax (pg/mL)	(Ref) Moderate (Test) vs Normal (Ref) Severea (Test) vs Normal	7 6 7	7 7 7	2.36 3.03 2.90	2.01 2.01 2.01	1.177 1.510 1.445	1.510) (1.145, 1.992) (1.128,
	(Ref)						1.852)
	Mild (Test) vs Normal						(0.860,
AUCt (h*pg/m L)	(Ref) Moderate (Test) vs Normal (Ref) Severe8 (Test) vs Normal	7 6 7	7 7 7	221 245 388	203 203 203	1.089 1.207 1.907	1.379) (0.929, 1.568) (1.508,
	(Ref)						2.411)
	Mild (Test) vs Normal						(0.858,
AUCinf (h*pg/m L)	(Ref) Moderate (Test) vs Normal (Ref) Severea (Test) vs Normal	7 5 7	7 7 7	223 240 394	204 204 204	1.093 1.180 1.932	1.392) (0.895, 1.556) (1.521,
	(Ref)						2.456)

The log-transformed PK parameters (C_max, AUC_b and AUCinf) are analyzed using a linear mixed-effect model, with fixed effect for hepatic impairment group and âge and weight as covariates.______________________________________________________________________________ a. For subjects with severe hepatic impairment AUC and C_max were adjusted for dose. Dose adjusted concentration = (concentration/600 mg) x 1500 mg.

[0153] Plots of individual treatment ratios of PK parameters of voxelotor in whole blood and 5 plasma by hepatic impairment status group are presented in FIG. 5 and FIG. 6 respectively.

FIGS. 5-6 show the comparisons of Mild vs Normal; Moderate vs Normal; Severe vs Normal;

and Severe(Dose Adjusted) vs Normal.

[0154] The exposure in ternis of AUC for voxelotor in plasma was 9% to 21 % higher in subjects with mild and moderate hepatic impairment compared to subjects with normal hepatic fonction, voxelotor exposures in terms of plasma AUC adjusted for dose was 90% to 93% higher in subjects with severe hepatic impairment compared to subjects with normal hepatic fonction. In 5 comparison to subjects with normal hepatic fonction, the Cmax was 18%, 51 %, and 45% higher in subjects with mild, moderate, and severe hepatic impairment, respectively (C_max was adjusted for dose for the severe hepatic impairment group).

[0155] The médian t_max was similar for ail of the hepatic fonction groups. Subjects with normal hepatic fonction, mild, and moderate hepatic impairment had a similar ti/z and CL/F. In comparison, the tj/2 was longer and the CL/F was lower in subjects with severe hepatic impairment.

[0156] The fraction unbound of voxelotor measured at the 4-hour timepoint was similar across ail groups. The unbound parameters therefore showed similar results to the bound parameters.

[0157] Pharmacokinetic conclusions: Whole blood and plasma voxelotor exposures were

87% to 93% higher in subjects with severe hepatic impairment compared to subjects with normal hepatic fonction, while subjects with mild to moderate hepatic impairment were only 9% to 21% higher compared to subjects with normal hepatic fonction. Based on this increase in exposure in subjects with severe hepatic impairment, a dose adjustment is warranted in these subjects. No dose adjustment is warranted in subjects with mild to moderate hepatic impairment.

Safety évaluation

[0158] As shown herein, voxelotor was safe and well tolerated when administered as a single oral dose of 1500 mg to subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and subjects with normal hepatic fonction, or 600 mg to subjects with severe (Child-Pugh C) hepatic 25 impairment.

[0159] No deaths, other serious adverse events (SAEs), and no AEs leading to discontinuation of the study were reported.

[0160] Overall, 11 subjects (39.3%) reported i 7 TEAEs over the course of the study, among which 15 were considered mild and 2 were considered moderate. The most frequently reported

TEAE (in 3 or more subjects overall) was diarrhea (7 events m 7 subjects [25% of subjects]). The 17 TEAEs occurred only in subjects with mild, moderate, or severe hepatic impairment status.

[0161J Subjects with mild hepatic impairment: 4 of 7 subjects (57.1%) reported mild TEAEs.

A total of 7 mild TEAEs (diarrhea [2 events], dyspepsia [2 events], sinus tachycardia, ligament sprain, and headache) were reported.

[0162] Subjects with moderate hepatic impairment: 5 of 7 subjects (71.4%) reported mild TEAEs, and 1 of 7 subjects (14.3%) reported a moderate TEAE. A total of 7 mild TEAEs (diarrhea [5 events], vomiting, and influenza) and 1 moderate TEAE (nephrolithiasis) were reported.

[0163] Subjects with severe hepatic impairment: 1 of 7 subjects (14.3%) reported a mild TEAE and a moderate TEAE. A total of 1 mild TEAE (pyrexia) and 1 moderate TEAE (dyspnoea) were reported.

[0164] Subjects with normal hepatic function: No TEAEs were reported.

[0165] Seven subjects (25.0%) reported 8 TEAEs which were considered by the investigator to be possibly/probably related to study drug. These included 6 events of diarrhea, 1 event of dyspepsia, and 1 event of headache.

[0166] With the exception of 2 mild TEAEs (headache and dyspepsia) and 1 moderate TEAE (dyspnoea), ail other TEAEs resolved without requiring any treatment.

Example 2

[0167] The effect of voxelotor on the pharmacokinetics (PK) of a single dose of caffeine, warfarin sodium, omeprazoie, and midazolam hydrochloride, which are probe substrates for cytochrome P450 (CYP)1A2, CYP2C9, CYP2C19, and CYP3A4, respectively, were studied in healthy subjects. During Period 1, subjects received a single dose of caffeine 100 mg, warfarin sodium 10 mg + vitamin K 10 mg, omeprazoie 20 mg, and midazolam hydrochloride 2 mg on Day 1. During Period 2, subjects received voxelotor 900 mg QD on Days 1 and 2 followed by 600 mg QD on Day 3, a single dose of caffeine 100 mg, warfarin sodium 10 mg + vitamin K 10 mg, omeprazole 20 mg, and midazolam hydrochloride 2 mg on Day 4, and voxelotor 600 mg QD on Days 4 through 7.

[0168] Whole blood and plasma concentrations of voxelotor and plasma concentrations of caffeine, paraxanthine, S-warfarin, omeprazole, 5-hydroxyomeprazole, midazolam, and 15 hydroxymidazolam were determined using validated assays. Pharmacokinetic variables were calculated from the whole blood and plasma concentrations using noncompartmental methods including: maximum observed plasma concentration (Cmax), area under the plasma concentrâtiontime curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC_t), AUC from time 0 extrapolated to infinity (AUCmt), the time that C_max was observed (t_max), and terminal élimination half-life (1½) for caffeine, paraxanthine, S-warfarin, omeprazole, 5hydroxy omeprazole, midazolam, and 1-hydroxymidazolam; ratio of métabolite to parent Cmax, AUC_t, and AUC_mf corrected for molecular weight for paraxanthine/caffeine, 5hydroxyomeprazole/omeprazole, and 1-hydroxymidazolam/midazolam in plasma; and C_max. tmax, AUC from time 0 to 24 hours (Days 4 and 7), and 1½ (Day 7) for voxelotor in whole blood and 15 plasma.

[0169) The effect of multiple doses on voxelotor on the PK of probe substrates for CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam) and métabolites paraxanthine, 5-hydroxyomeprazole, and 1-hydroxymidazolam is presented in Figure 7.

[0170] From these studies, it was determined that the administration of voxelotor had no clinically meaningful effect on the PK of probe substrates for CYP1A2 (caffeine), CYP2C9 (Swarfarin), or CYP2C19 (omeprazole). Overall exposure of the CYP3A4 probe substrate (midazolam) was increased by 63% in the presence of voxelotor. The overall exposure of the midazolam métabolite, 1 ’-hydroxy-midazolam, was increased by 75% in the presence of voxelotor. Whole blood voxelotor exposure was approximately 20 to 25 tîmes higher than plasma voxelotor exposure. Voxelotor was safe and well tolerated when administered alone and in combination with caffeine, warfarin sodium, omeprazole, and midazolam hydrochloride to heaithy subjects.

[0171] A CYP3A4-mediated time dépendent inhibition PBPK model (described in Example 30 3) was used to simulate the effects of voxelotor on the kinetics of midazolam. Specifically,

simulated plasma concentrations of midazolam in the absence and presence of voxelotor ( 1500 mg QD) in patients with sickle cell disease were performed. The results are shown in Table F.

[0172] Based on this data, it is contemplated that voxelotor is a moderate inhibitor of CYP3A4.

Table F. Simulated Géométrie Mean Ratios forC_max and AUC of midazolam in the absence and presence of voxelotor (1500 mg QD) in patients with SCD

	Control Cmax AUC (ng/mL) (ng/mL*h)	Presence of Voxelotor Cmax ’ AUC (ng/mL) (ng/mL*h)	Ratio Cmax AUC
Simulated	7.04 22.23	14.44 69.67	2.05 3.13 (2.02-2.17) (2.95-3.47)

Example 3

[0173] PBPK modeling and simulation was also used to evaluate voxelotor as an object (victim) of drug interactions.

[0174] The relative contributions of enzymes to the formation of oxidative, glucuronidation, and réduction products of voxelotor were assigned on the basis of in vitro metabolism data and in vivo mass balance/metabolite profile data from previous studies, and a base model for PK in 15 heaîthy subjects was developed using previous single-dose PK studies. Model vérification was performed using clinical datasets from previous multiple-dose DDI studies in heaîthy subjects.

Such previous studies were carried out according to methods known in the art. Subsequently, the model was refined and adjusted to describe the PK of voxelotor in subjects with sickle cell disease. Literature data on biochemical and physiological parameters likely to be affected by the 20 disease and clinical data were used.

[0175] A PBPK model incorporated in a Simcyp simulator that considers both liver and intestinal metabolism was used, as it described the disposition of voxelotor with reasonable accuracy when compared with clinical data. The modeling studies were performed using a dose of 1500 mg of voxelotor.

[0176] Results for modeling studies of voxelotor, administered in a single dose, in the absence and presence of CYP3A4 modulators are summarized in Table G. Results for modeling studies of voxelotor, administered in multiple doses, in the absence and presence of CYP3A4 modulators are summarized in Table H. In these tables, “fmCYP3A4” refers to fraction metabolized by CYP3A4.

Table G. Predicted Géométrie Mean (GM) Ratios* for Plasma and Whole Blood C_max and AUC of Voxelotor (Single Dose) in the Absence and Presence of CYP3A4 Modulators (Multiple Dose) in SCD patients

CYP3A4 Modulator	Ratio
	GM Cmax	GM AUC
Kétoconazole (400 mg) Strong CYP3A4 inhibitor	1.05 (1.04-1.05)	1.83 (1.75-1.91)
Fluconazole (400 mg) Moderate CYP3A4 inhibitor	1.05 (1.04-1.05)	2.16 (2.09-2.24)
Fluconazole (200 mg) Moderate CYP3A4 inhibitor	1.04 (1.04-1.04)	1.84 (1.79-1.89)
Fluvoxamine (50 mg) Weak CYP3A4 inhibitor	1.02 (1.01-1.02)	1.20 (1.19-1.22)
Rifampicin (600 mg) Strong CYP3A4 inducer	0.86 (0.84-0.87)	0.28 (0.26-0.30)
Efavirenz (600 mg) Moderate CYP3A4 inducer	0.94 (0.93-0.94)	0.46 (0.44-0.50)

* Géométrie mean ratios for whole blood are identical; assumes fmCYP3A4 0,75.

Table H. Predicted Géométrie Mean (GM) Ratios* for Plasma and Whole Blood Cmax and AUC of Voxelotor (Multiple Doses) in the Absence and Presence of CYP3A4 Modulators (Multiple Dose) in SCD patients

CYP3A4 Modulator	Ratio
	GM Cmax	GM Cmin	GM AUC
Kétoconazole (400 mg) Strong CYP3A4 inhibitor	1.40 (1.35-1.45)	1.52 (1.46-1.59)	1.46 (1.46-1.59)
Fluconazole (400 mg) Moderate CYP3A4 inhibitor	1.70 (1.64-1.77)	1.94 (1.85-2.04)	1.80 (1.73-1.88)
Fluconazole (200 mg) Moderate CYP3A4 inhibitor	1.55 (1.51-1.60)	1.74 (1.67-1.82)	1.63 (1.58-1.69)
Fluvoxamine (50 mg) Weak CYP3A4 inhibitor	1.22 (1.19-1.24)	1.28 (1.25-1.31)	1.24 (1.22-1.27)
Rifampicin (600 mg) Strong CYP3A4 inducer	0.33 (0.31-0.35)	0.11 (0.09-0.14)	0.23 (0.21-0.25)
Efavirenz (600 mg) Moderate CYP3A4 inducer	0.48 (0.44-0.51)	0.31 (0.28-0.35)	0.40 (0.37-0.44)

*Geometric mean ratios for whole blood are identical; assumes fmCYP3A4 0.75.

|0177] Based on the above data, it is contemplated that co-administration of moderate or strong CYP3A4 inducers can decrease voxelotor plasma and whole blood exposures (Cmin, Cmax, and AUC), which can thereby reduce the efficacy of voxelotor. It is further contemplated that coadministration of strong CYP3A4 inhibitors can increase plasma and whole blood exposures (Cmax and AUC).

Example 4

Indications and Usage

[0178] OXBRYTA is indicated for the treatment of sickle cell disease (SCD) in adults and pédiatrie patients 12 years of âge and older.

[0179] This indication is approved under accelerated approval based on increase in hemoglobin (Hb) [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon vérification and description of clinical benefit in confirmatory trial(s).

Dosage and Administration

2.1 Recommended Dosage for Sickle Cell Disease

[0180] The recommended dosage of OXBRYTA is 1,500 mg taken orally once daily with or without food. If a dose is missed, continue dosing on the day following the missed dose.

[01811 Patients should swallow OXBRYTA tablets whole. Do not eut, crush, or chew the tablets. OXBRYTA may be given with or without hydroxyurea.

2.2 Recommended Dosage for Hepatic Impairment

[0182] The recommended dosage of OXBRYTA in patients with severe hepatic impairment (Child Pugh C) is 1,000 mg taken once daily with or without food. No dosage adjustment of OXBRYTA îs required for patients with mild or moderate hepatic impairment [see Use in Spécifie Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Recommended Dosage of OXBRYTA When Used with Concomitant

Moderate or Strong Inducers, Strong Inhibîtors of CYP3A4, or Fluconazole

[0183] Avoid concomitant use of strong or moderate CYP3A4 inducers, strong CYP3A4 inhibîtors, or fluconazole with OXBRYTA [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. If concomitant use of strong or moderate CYP3A4 inducers, strong 20 CYP3A4 inhibîtors, or fluconazole is unavoidable, adjust the OXBRYTA dosage as recommended in Table 1.

Table 1 : OXBRYTA Recommended Dosage for Concomitant Médications

Concomitant Médication	Recommended OXBRYTA Dosage
Strong CYP3A4 inhibîtors or fluconazole	1,000 mg once daily
Strong or moderate CYP3A4 inducers	2,500 mg once daily

Dosage Forms and Strengths

[0184] Tablets: 500 mg light yellow to yellow, oval shaped, biconvex, debossed with “GBT 500” on one side.

Contraindications

[0185] OXBRYTA is contraindicated in patients with a history of serions drug hypersensitivity reaction to voxelotor or excipients. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Warnings and Précautions (5.1), and Adverse Reactions (6.1)].

Warnings and Précautions

5.1 Hypersensitivity Réactions

[0186] Serions hypersensitivity reactions after administration of OXBRYTA hâve occurred in <1% of patients treated. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Adverse Reactions (6.1)].

[0187] If hypersensitivity reactions occur, discontinue OXBRYTA and administer appropriate medical therapy. Do not reinitiate OXBRYTA in patients who expérience these symptoms with previous use.

5.2 Laboratory Test Interférence

[0188] OXBRYTA administration may interfère with measurement of Hb subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography (HPLC) [see Drug Interactions (7.3)]. If précisé quantitatîon of Hb species is required, chromatography should be performed when the patient is not receiving OXBRYTA therapy.

Adverse Reactions

[0189] The following clinically significant adverse reaction is discussed in other sections of the labeling: Hypersensitivity Reactions [see Contraindications (4)].

6.1 Clinical Trials Expérience

[0190] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

[0191] The safety of OXBRYTA was evaluated in the HOPE trial based upon 88 patients who received OXBRYTA 1,500 mg and 91 patients who received placebo orally once daily [see Clinical Studies (14)~\. Seventy-four patients received OXBRYTA 1,500 mg once daily for >24 weeks and 65 patients for >48 weeks.

[0192] In patients who received OXBRYTA 1,500 mg once daily the médian âge was 24 10 years (range: 12-59); 65% female; 66% Black or African American and 23% Arab/Middle Eastern; and 65% receiving hydroxyurea at baseline.

[0193] Serious adverse reactions occurred in 3% (3/88) of patients receiving OXBRYTA 1,500 mg, which included headache, drug hypersensitivity, and pulmonary embolism occurring in 1 patient each. Permanent discontinuation due to an adverse reaction (Grades 1-4) occurred in 15 5% (4/88) of patients who received OXBRYTA 1,500 mg.

[0194] Dosage modifications (dose réduction or dosing interruption) due to an adverse reaction occurred in 41% (36/88) of patients who received OXBRYTA. Most frequent adverse reactions requiring dosage interruption occurring in more than one patient who received OXBRYTA 1,500 mg included diarrhea, headache, rash, and vomiting.

[0195] The safety profile observed in pédiatrie patients 12 to <17 years of âge treated with

OXBRYTA was similar to that seen in adult patients.

[0196] The most commun adverse reactions occurring in >10% of patients treated with OXBRYTA 1,500 mg with a différence of >3% compared to placebo are summarized in Table 2.

Table 2: Adverse Reactions (>10%) in Patients Receiving OXBRYTA with a Différence

Between Arms of >3% Compared to Placebo in HOPE

Adverse Reaction a	OXBRYTA 1,500 mg (N=88)	Placebo (N=91)
Headache	23 (26%)	20 (22%)
Diarrhea	18(20%)	9 (10%)
Abdominal Pain b	17(19%)	12(13%)
Nausea	15 (17%)	9(10%)
Fatigue	12(14%)	9(10%)
Rash c	12(14%)	9(10%)
Pyrexia	11 (12%)	6 (7%)

^a Adverse reactions were Grades I or 2 except for Grade 3 diarrhea (l), nausea (1), rash (I), and rash generalized (3) b Abdominal pain (grouped PTs) included the following PTs: abdominal pain and upper abdominal pain ^c Rash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, maculopapular rash, pruritic rash, papular rash, erythematous rash, and vesicular rash

[0197] Ciinically relevant adverse reactions occurring in <10% of patients included:

• Drug hypersensitivity

Drug Interactions

7.1 Effect of Other Drugs on Voxelotor

Strong CYP3A4 Inhibitors or Fluconazole

[0198] Co-administration of strong CYP3A4 inhibitors or fluconazole may increase voxelotor plasma concentrations and may lead to increased toxicity.

[0199] Avoid co-administration of OXBRYTA with strong CYP3A4 inhibitors or fluconazole and replace these drugs with alternative drugs when possible [see Clinical Pharmacology (12.3)]. Decrease the OXBRYTA dosage when co-administration with a strong 20 CYP3A4 inhibîtor or fluconazole is unavoidable [see Dosage and Administration (2.3)].

Strong or Moderate CYP3A4 Inducers

[0200] Co-administration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma concentrations and may lead to reduced efficacy.

[0201] Avoid co-administration of OXBRYTA with strong or moderate CYP3A4 inducers.

Increase the OXBRYTA dosage when co-administration with a strong or moderate CYP3A4 inducer is unavoîdable [see Dosage and Administration (2.3)}

7.2 Effect of Voxelotor on Other Drugs

[0202] Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate) [see Clinical P harmacology (12.3)}. Avoid co-administration of OXBRYTA with sensitive C YP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoîdable, consider dose réduction of the sensitive CYP3A4 substrate(s).

7.3 Laboratory Test Interférence

[0203] OXBRYTA administration may interfère with measurement of Hb subtypes (HbA, HbS, and HbF) by HPLC [see Warnings and Précautions (5.2)}. If précisé quantitation of Hb 15 species is required, chromatography should be performed when the patient is not receiving OXBRYTA therapy.

Use in Spécifie Populations

8.1 Pregnancy

Risk Summarv

[0204J There are no available data on OXBRYTA use in prégnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternai or fêtai outcomes. In animal reproduction studies, oral administration of voxelotor to prégnant rats and rabbits during organogenesis at exposures up to 2.8-times (rats) and 0.3-tîmes (rabbits) the exposure at the maximum recommended human dose resulted in no adverse developmental effects (see Data).

[0205] The estimated background risk of major birth defects and miscarriage for the indicated population is approximately 14% and up to 43%, respectively. Ail pregnancies hâve a background risk of birth defect, loss, or other adverse outcomes.

[0206] There are adverse effects on maternai and fêtai outcomes associated with sickle cell disease in pregnancy (see Clinical Considérations). OXBRYTA should only be used during pregnancy if the benefit of the drug outweighs the potential risk.

Ciinical Considérations

Disease-Associated Maternai and/or Embryo/Fetal Risk

[0207] Women with sickle cell disease hâve an increased risk of adverse pregnancy outcomes for the mother and the fétus. Prégnant women are at greater risk for vasoocclusive crises, pre-eciampsia, eclampsia, and maternai mortality. For the fétus, there is an increased risk for intrauterine growth restriction, preterm delivery, low birth weight, and périnatal mortality.

Data

Animal Data

[0208] In embryo-fetal development studies, voxelotor was administered orally to prégnant rats at 15, 50, and 250 mg/kg/day (gestation days 7 through 17) and rabbits at 25, 75, and 150 mg/kg/day (gestation days 7 through 19) through organogenesis. Maternai toxicity was observed 15 at the highest dose levels in these studies équivalent to 2.8-times (rats) and 0.3-times (rabbits) the exposures in patients receiving OXBRYTA at the recommended daily dose. There was no evidence of adverse developmental outcomes in rats or rabbits.

[0209] In a pre- and postnatal development study, voxelotor was administered orally to prégnant rats at 15, 50 and 250 mg/kg/day (gestation day 6 through lactation day 20). Maternai 20 gestational body weights were decreased at 250 mg/kg/day, which continued to the end of lactation. The findings in offspring included reduced survival and reduced body weights throughout lactation, weaning and maturation. The effects in offspring were observed at the maternai dose of 250 mg/kg/day with an exposure approximately 2.8-times the exposure in patients at the recommended dose.

8.2 Lactation

Risk Summary

[0210] There are no data on the presence of voxelotor in human milk, the effects on the breastfed child, or the effects on milk production. Voxelotor was detected in milk in lactating rats. Plasma concentrations of voxelotor in prégnant rats were higher than the concentration in milk. When a drug is présent in animal milk, it is likely that the drug will be présent in human milk. The concentration of voxelotor in animal milk does not necessarily predict the concentration of drug tn human milk. Because of the potential for serious adverse reactions in the 5 breastfed child, including changes in the hematopoietic system, advise patients that breastfeeding is not recommended during treatment with OXBRYTA, and for at least 2 weeks after the last dose.

8.4 Pédiatrie Use

[0211] The safety and effectiveness of OXBRYTA for sickle cell disease hâve been established in pédiatrie patients aged 12 years and older. Use of OXBRYTA for sickle cell disease is supported by evidence from an adéquate and well-controlled study in adults and pédiatrie patients (HOPE trial). The HOPE trial enrolled a total of 26 pédiatrie patients aged 12 to <17 years, in which 12 pédiatrie patients received OXBRYTA 1,500 mg once daily and 14 pédiatrie patients received OXBRYTA 900 mg once daily [see Adverse Reactions (6.1), Clinical

IS Pharmacology (12.3), and Clinical Studies (14)]. The safety and efficacy of OXBRYTA in pédiatrie patients below the âge of 12 years hâve not been established.

[0212] Pharmacokinetics, safety and efficacy in pédiatrie patients 12 years to <17 years were similar to that observed în adults [see Dosage and Administration (2), Clinical Pharmacology (12.3) and Clinical Studies (14)].

[0213] The adverse reactions observed in pédiatrie patients 12 to <17 years treated with

OXBRYTA were similar in type and frequency to those observed in adults [see Adverse Reactions (6.1)].

8.5 Gériatrie Use

[0214] Clinical studies of OXBRYTA did not include sufïïcient numbers of subjects aged 65 25 and over to détermine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

[0215] Severe hepatic impairment increases voxelotor exposures [see Clinical Pharmacology (12.3)]. Reduce OXBRYTA dose [see Dosage and Administration (2.2)].

Description

[0216] Voxelotor is a hemoglobin S polymerization inhibitor. The Chemical name of voxelotor is: 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-y!)pyridin-3-yl)methoxy)benzaldehyde.

Voxelotor has a molecular formula of C19H19N3O3 and a molecular weight of 337.4. The Chemical structure of voxelotor is:

'''''OH

[0217] Voxelotor, the active drug substance, is a white-to-yellow-to-beige compound in crystalline Form II of its free base. It is non-hygroscopic. It is highly soluble in common organic solvents such as acetone and toluene and insoluble in water (approximately 0.03 mg/mL).

[0218] Each OXBRYTA film-coated tablet for oral use contains 500 mg of voxelotor with the following inactive ingrédients: colloïdal Silicon dioxide, croscarmellose sodium, magnésium stéarate, microcrystalline cellulose, and sodium lauryl sulfate. In addition, the film coating contains: polyethylene glycol 3350, poiyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

Clinical Pharmacology

12,1 Mechanism of Action

[0219] Voxelotor is a hemoglobin S (HbS) polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to red blood cells (RBCs). By increasing the affinity of Hb for oxygen, voxelotor demonstrates dose-dependent inhibition of HbS polymerization. Nonclinical studies suggest that voxelotor may inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity.

12.2 Pharmacodynamies

[0220] The pharmacodynamie effect of voxelotor treatment demonstrated a dose-dependent increase in Hb oxygen affinity as determined by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was lînearly correlated with voxeiotor exposure.

[0221] The pharmacodynamie effect of voxelotor treatment also demonstrated a dosedependent réduction in clinical measures of hemolysîs (indirect bilirubin and % réticulocytes).

Cardiac Electrophysiology

[0222] At plasma concentrations approximately 2-fold above therapeutic concentrations, voxelotor does not prolong QT interval to any clmically relevant extent.

12.3 Pharmacokinetics

[0223] Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to îts preferential binding to Hb. The major route of élimination of voxelotor is by metabolism with subséquent excrétion of métabolites into urine and feces. The P K are linear and voxelotor exposures increased proportionally with either single or multiple doses (Table 3) in whole blood, plasma, and RBCs. Steady-state after repeated administration is reached within 8 days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD.

Table 3: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole Blood

PK Parameter	Voxelotor 1,500 mg Géométrie Mean (%CV)
Plasma PK
AUCo-24h (gghr/mL)	246 (27.7)
Cmax(pg/mL)	12.6 (24.8)
Half-life (hours)	35.5 (25)
Whole Blood PK
AUCo-24h (gg'hr/mL)	3820 (35)
Cmax(gg/mL)	___________________179 (33.1)__________________

Absorption

[0224] The médian plasma and whole blood T_max of voxelotor after oral administration is 2 hours. The mean peak concentrations in whole blood and RBCs are observed between 6 and 18 hours after oral administration.

Effect of Food

[0225] A high-fat, high-calorie meal increased voxelotor AUC by 42% and C_max by 45% in whole blood relative to AUC and C_max in the fasted State. Similarly, AUC increased by 42% and Cmax increased by 95% in plasma.

Distribution

[0226] Voxelotor apparent volume of distribution of the central compartment and peripheral compartment are 338 L and 72.2 L in plasma, respectively. Proteîn binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 15:1 in patients with SCD.

Elimination

[0227] The géométrie mean (%CV) terminal élimination half-life of voxelotor in patients with SCD is 35.5 hours (25%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as 6.7 L/h in plasma in patients with SCD.

Metabolism

[0228] In vitro and in vivo studies indicate that voxelotor is extensively metabolîzed through

Phase I (oxidation and réduction), Phase II (glucuronidation) and combinations of Phase 1 and II metabolism. Oxidation of voxelotor is mediated primarily by CYP3A4, with minor contribution from CYP2C19, CYP2B6, and CYP2C9.

Excrétion

[0229] Following the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its métabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged).

Spécifie Populations

[0230] No clinically significant différences în the pharmacokinetics of voxelotor were 25 observed based on âge (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe rénal impairment (créatinine clearance [CLcr] 15-89 mL/min).

Pédiatrie Patients

[0231] The pharmacokinetic parameters of voxelotor were similar in pédiatrie patients 12 to <17 years and adults.

Patients with Rénal Impairment

[0232] There was no clinically signîficant effect of rénal fonction on the excrétion of voxelotor. Following a single 900 mg dose of voxelotor, whole blood exposures în subjects with severe rénal impairment (eGFR <30 mL/min/l .73 m²) were 25% lower compared to healthy Controls.

[0233] The unbound plasma concentrations were comparable. OXBRYTA has not been evaluated in patients with end stage rénal disease requiring dialysis.

Patients with Hepatic Impairment

[0234] The voxelotor AUC in whole blood were 14% and 15% higher in subjects with mild and moderate hepatic impairment (Chîld Pugh A and B) and 90% higher in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic fonction.

Patients with HbSC Génotype

[0235] Voxelotor steady State whole blood AUC and Cmax were 50% and 45% higher in HbSC génotype patients (n= 11) compared to HbSS génotype (n=220) patients and voxelotor steady State plasma AUC and Cmax were 23% and 15% higher in HbSC génotype patients compared to HbSS génotype patients.

Drug Interaction Studies

Clinical Studies and Model-Infbrmed Approaches

[0236] Effect ofStrong CYP3A4 Inhibitors on Voxelotor: concomitant use of OXBRYTA with kétoconazole is predicted to increase voxelotor AUC in patients by 42% to 83%.

[0237] Effect ofStrong or Moderate CYP 3 A4 Inducers on Voxelotor·. concomitant use of

OXBRYTA with rifampin (a strong CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 77%, and efavirenz (a moderate CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 60%.

[0238] Effect of Fluconazole on Voxelotor: concomitant use of OXBRYTA with fluconazole, a moderate CYP3A4 inhibitor, a moderate CYP2C9 inhibitor and a strong CYP2C19 inhibitor, is predîcted to increase voxelotor AUC in patients by 40% to 116%.

[0239] Effect of Acid Reducing Agents on Voxelotor: co-administration of omeprazole (proton pump inhibitor) with OXBRYTA did not alter voxelotor exposure.

[0240] Effect of Voxelotor on CYP450 Enzymes: in vivo voxelotor inhibits CYP3A4, but not CYPl A2, CYP2C9, CYP2C19, CYP2C8, or CYP2D6. The observed exposure increase of the CYP3A4 substrate midazolam in healthy subjects was 1.6-fold and the predicted increase in patients after multiple dosing is 2-fold.

[02411 Effect of Voxelotor on P-gp~ concomitant use of OXBRYTA with digoxin (a P-gp substrate) did not alter digoxin to a clinically relevant extent.

In Vitro Etudiés

[0242] CYP Enzymes: voxelotor is a réversible and time-dependent inhibitor as well as an inducer of CYP2B6.

[0243] Transporter Systems·, voxelotor is not an inhibitor of P-gp, BCRP, OATP1B1,

OATP1B3, OCT2, OAT1, OAT3, MATEI, MATE2-K, or BSEP. Voxelotor is not a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP.

Nondinical toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

[0244] Voxelotor was not carcinogenic in a 26-week study in RasH2 transgenic mice at oral doses of30, 150, or 500 mg/kg/day.

[0245] Voxelotor was not genotoxîc in the reverse mutation bacterial (Ames) test, rat Cornet assay, or rat micronucleus assay.

[02461 In a fertility' and early embryonic development study, voxelotor was administered 25 orally to rats at 15, 50, and 250 mg/kg/day. Males were dosed 28 days prior to mating through cohabitation and females were dosed 14 days prior to mating through gestation Day 7. Voxelotor had no effect on fertility or reproductive function. Sperm motility was decreased and changes in sperm morphology occurred at 250 mg/kg/day (approximately 5-times the human exposure at 1,500 mg/day).

Clinical Studies

[0247] The efficacy and safety of OXBRYTA in sickle cell disease (SCD) was evaluated in HOPE, a randomized, double-blind, placebo-controlled, multicenter trial [NCT 03036813], In this study, 274 patients were randomized to daily oral administration of OXBRYTA 1,500 mg (N=90), OXBRYTA 900 mg (N=92), or placebo (N =92). Patients were included if they had from 1 to 10 vasoocclusive crisis (VOC) events within 12 months prior to enrollment and baseline hemoglobin (Hb) >5.5 to <10.5 g/dL. Eligible patients on stable doses of hydroxyurea for at least 90 days were allowed to continue hydroxyurea therapy throughout the study. Randomization was stratified by patients already receiving hydroxyurea (yes, no), géographie région (North America, Europe, Other), and âge (12 to <17 years, i 8 to 65 years). The trial excluded patients who received red blood cell (RBC) transfusions within 60 days and erythropoietin within 28 days of enrollment, had rénal insufficiency, uncontrolled liver disease, were prégnant, or lactating.

[0248] The majority of patients had HbSS or HbS/beta°-thalassemia génotype (90%) and were receiving background hydroxyurea therapy (65%). The médian âge was 24 years (range: 12 to 64 years); 46 (17%) patients were 12 to <17 years of âge. Médian baseline Hb was 8.5 g/dL (5.9 to 10.8 g/dL). One hundred and fifteen (42%) had 1 VOC event and 159 (58%) had 2 to 10 events within 12 months prior to enrollment.

[0249] Efficacy was based on H b response rate defmed as a Hb increase of >1 g/dL from baseline to Week 24 in patients treated with OXBRYTA 1,500 mg versus placebo. The response rate for OXBRYTA 1,500 mg was 51.1% (46/90) compared to 6.5% (6/92) in the placebo group (p < 0.001). No outlier subgroups were observed. The distribution of Hb change from baseline for individual patients completing 24 weeks of treatment with OXBRYTA 1,500 mg or placebo is depicted in Figure 8.

[0250] Additional efficacy évaluation included change in FIb and percent change in indirect bilirubin and percent réticulocyte count from baseline to Week 24 (Table 4).

Table 4: Adjusted Mean (SE) Change from Baseline to Week 24 in Hemoglobin and Clinical Measures of Hemolysis

	OXBRYTA 1,500 mg QD (N-00)	Placebo (N=92)	P Value
Hemoglobin	1.14 g/dL (0.13)	-0.08 g/dL (0.13)	<0.001
Indirect Bilirubin	-29.08 % (3.48)	-3.16% (3.52)	<0.001
Percent Réticulocyte Count	-19.93 % (4.60)	4.54 % (4.60)	<0.001

16 How Supplied/Storage and Handling

[0251] The 500 mg tablet is film-coated, light yeliow to yeliow, oval shaped. biconvex, debossed with “GBT 500” on one side, and available in:

• Bottles of 90 tablets with child-resistant closure; NDC 72786-101-01

[0252] The bottle also contains one desiccant canister and one polyester coil. Do not eat.

Store at or below 30°C (86°F).

Patient Counseling Information

[0253] Advise the patient to read the FDA-approved patient labeling (Patient Information).

[0254] Advise patients that serions hypersensitivity reactions may occur, and to notify their healthcare providers if they develop generalîzed rash, urticaria, shortness of breath, facial swelling and eosinophilia [see Warnings and Précautions (5.1)}.

[0255] Advise women not to breastfeed while they are on OXBRYTA therapy [see Use in Spécifie Populations (8.2)].

Dosage and Administration

[0256] Advise patients to:

• Continue taking OXBRYTA every day for as long as their physician tells them. This is a long-term treatment.

• Swallow OXBRYTA tablets whole. Do not eut, crush, or chew the tablets.

• Take with or without food.

• If a dose is missed, continue dosing on the day following the missed dose [see Dosage and Administration (2.1)).

Table 5.

PATIENT INFORMATION

OXBRYTA™ (ox brye ta) (voxelotor) tablets

What is OXBRYTA?

OXBRYTA is a prescription medicine used for the treatment of sickle cell disease in adults and children 12 years of âge and older.

It is not known if OXBRYTA is safe and effective in children below 12 years ofage.

Do not take OXBRYTA if you hâve had an allergie reaction to voxelotor or any of the ingrédients in OXBRYTA. See the end of this leaflet for a list of the ingrédients in OXBRYTA. If you are receiving exchange transfusions, talk to your Healthcare provider about possible difficulties with the interprétation of certain blood tests when taking OXBRYTA.

Before taking OXBRYTA, tell your Healthcare provider about ail of your medical conditions, including if you:

• hâve liver problems * are prégnant or plan to become prégnant. It is not known if OXBRYTA can harm your unborn baby.

• are breastfeeding or plan to breastfeed. It is not known if OXBRYTA can pass into your breastmilk and if it can harm your baby. Do not breastfeed during treatment with OXBRYTA and for at least 2 weeks after the last dose.

Tell your healthcare provider about ail the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal suppléments. Some medicines may affect how OXBRYTA works. OXBRYTA may also affect how other medicines work.

Keep a list of ail your medicines and show it to your healthcare provider.

How should I take OXBRYTA?

• Take OXBRYTA exactly as your healthcare provider tells you.

• Do not change your dose or stop taking OXBRYTA unless your healthcare provider tells youto.

• Take OXBRYTA l time each day. Swallow each OXBRYTA tablet whole. Do not eut, crush or chew the tablets.

o Your healthcare provider may change your dose if needed.

• Your healthcare provider may also prescribe hydroxyurea during treatment with OXBRYTA.

• Take OXBRYTA with or without food.

• If you forget to take a dose of OXBRYTA, skip that dose and return to your normal dosing schedule the next day.

What are the possible side effects of OXBRYTA?

OXBRYTA can cause serions side effects, including:

Serious allergie reactions. Tell your healthcare provider or get emergency medical help right away if you get: • rash · shortness of breath • hives · sweiling of the face

The most common side effects of OXBRYTA include:

• headache · tiredness • diarrhea · rash ♦ stomach (abdominal) pain · fever • nausea

These are not ail the possible side effects of OXBRYTA.

Call your doctor for medical advice about side effects.

How should I store OXBRYTA?

Store OXBRYTA at or below 86°F (30°C).

OXBRYTA cornes in a child-resistant package.

The bottle contaîns a desiccant to help keep your medicine dry (protect it from moisture) and polyester coil. Do not eat.

Keep OXBRYTA and ail medicines out of the reach of children.

General information about the safe and effective use of OXBRYTA.

Medicines are sometimes prescribed for purposes other than those listed în a Patient Information leaflet. Do not use OXBRYTA for a condition for which it was not prescribed. Do not give OXBRYTA to other people, even if they hâve the same symptoms that you hâve. It may harm them. You can ask your Healthcare provider or pharmacist for information about OXBRYTA that is written for health professionals.

What are the ingrédients of OXBRYTA?

Active Ingrédient: voxelotor

Inactive Ingrédients: colloïdal Silicon dioxide, croscarmellose sodium, magnésium stéarate, microcrystalline cellulose, and sodium lauryl sulfate. The film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

Manufactured for: Global Blood Therapeutics, Inc. South San Francisco, CA 94080, USA. OXBRYTA is a trademark of Global Blood Therapeutics, Inc.

© 2019 Global Blood Therapeutics, Inc. Ail rights reserved.

[0257] Although the invention has been described with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the spécifie examples and studies detailed above are only illustrative of the invention. It should be understood that various 5 modifications can be made without departïng from the spirit of the invention. Accordingly, the invention is limited only by the following daims.

Claims (15)

1. Voxelotor for use in a method of treating sickle cell disease in a patient with severe hepatic impairment, wherein the voxelotor is for administration to the patient in a dosage of 500 mg to 1000 mg of voxelotor per day.

2. The voxelotor for use of claim 1, which is for administration to the patient in a dosage of 500 mg of voxelotor per day.

3. The voxelotor for use of claim 1, which is for administration to the patient in a dosage of 1000 mg of voxelotor per day.

4. The voxelotor for use of any one of claims 1-3, wherein the voxelotor is for administration with food.

5 patient a therapeutically effective amount of a strong or moderate CYP3A4 induccr and a dosage of voxelotor that is increased relative to a patient not taking a strong or moderate CYP3A4 inducer.

23. Voxelotor for use in a method of concurrently administering voxelotor and fluconazole or a strong CYP3A4 inhibitor, wherein the method comprises administering to a 10 patient a therapeutically effective amount of fluconazole or a strong CYP3A4 inhibitor and a dosage of voxelotor that is decreased relative to a patient not taking fluconazole or a strong CYP3A4 inhibitor.

24. The voxelotor for use of claim 23, wherein the dosage of voxelotor that is decreased is 1,000 mg per day.

28. A method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about ] 500 mg of voxelotor per day, and instructing the patient to avoid co-administration of a sensitive CYP3A4 substrate with a narrow' therapeutic index.

5

29. A method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein the patient is not co-administered a strong CYP3A4 inhibitor.

30. A method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein 10 the patient is not co-administered fluconazole.

31. A method of treating sickle cell disease in a patient in need thereof, comprising administering to the patient about 500 mg to about i 500 mg of voxelotor per day, and wherein the patient is not co-administered a moderate or a strong CYP3A4 inducer.

32. A method of treating sickle cell disease in a patient in need thereof, comprising 15 administering to the patient about 500 mg to about 1500 mg of voxelotor per day, and wherein the patient is not co-administered a sensitive CYP3A4 substrate with a narrow therapeutic index.

33. The method of any one of claims 25-32, wherein the patient is admînistered about 1500 mg of voxelotor per day.

34. A method of administering voxelotor to a patient in need thereof, comprising 20 administering to the patient a therapeutically effective amount of voxelotor, and advising the patient one or more of the following:

(a) advising the patient that a sensitive CYP3A4 substrate with a narrow therapeutic index, moderate CYP3A4 inducer, strong CYP3A4 inducer, fluconazole, or strong CYP3A4 inhibitor should be avoided or discontinued;

25 (b) advising the patient that co-administration of voxelotor with a sensitive CYP3A4 substrate with a narrow therapeutic index, moderate CYP3A4 inducer, strong CYP3A4 inducer, fluconazole, or strong CYP3A4 inhibitor can alter the therapeutic effect of voxelotor;

(c) advising the patient that co-administration of voxelotor and a moderate CYP3A4 inducer or strong CYP3A4 inducer can decrease voxelotor plasma concentrations and may lead to reduced effîcacy;

(d) advising the patient that co-administration of voxelotor and a strong CYP3A4 5 inhibitor can increase voxelotor plasma concentrations and may lead to increased toxicity;

(e) advising the patient that co-administration of voxelotor with a sensitive CYP3A4 substrate with a narrow therapeutic index can increase the systemic exposure of the sensitive CYP3A4 substrate with a narrow therapeutic index;

(f) advising the patient to replace a strong CYP3A4 inhibitor or fluconazole with an 10 alternative drug;

(g) if co-administration of a strong CYP3A4 inhibitor or fluconazole is unavoidable, decreasing the dose of voxelotor to 1000 mg per day;

(h) if co-administration of a moderate CYP3A4 inducer or strong CYP3A4 inducer is unavoidable, increasing the dose of voxelotor to 2500 mg per day; or

5. The voxelotor for use of any one of claims 1-3, wherein the voxelotor is for administration without food.

6. The voxelotor for use of any one of claims 1-3, wherein the voxelotor is for administration to the patient after fasting for about 10 hours.

7. The voxelotor for use of any one of claims 1-3, wherein the patient does not eat any food within about 4 hours after voxelotor is administered to the patient.

8. The voxelotor for use of any one of claims 1-7, wherein the patient has a Child-Pugh score of 10-15 points.

9. The voxelotor for use of claim 8, wherein the patient has a Child-Pugh score of 12-15 points.

10. The voxelotor for use of any one of claims 1-9, wherein the patient suffers from a chronic liver disease.

11. The voxelotor for use of any one of claims 1-9, wherein the patient suffers from a condition selected from the group consisting of liver fibrosis, cirrhosis, hepatocellular carcinoma, hepatic inflammation, hepatic steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), portai hypertension, hepatic encephalopathy, hepatitis, and any combination thereof.

12. The voxelotor for use of any one of claims 1-11, wherein the voxelotor is for administration to the patient once daily.

13. The voxelotor for use of any one of claims 1-12, wherein the voxelotor is for administration to the patient in an oral formulation.

14. The voxelotor for use of claim 13, wherein the oral formulation is a tablet.

15. The voxelotor for use of any one of claims 1-14, wherein the voxelotor is for administration to the patient in a single oral dosage of two tablets daily.

16. Voxelotor for use in a method of treating sickle cell disease in a patient that has mild or moderate hepatic impairment, wherein the voxelotor is for administration to the patient in a dosage of 1500 mg of voxelotor once daily.

17. Voxelotor for use in a method of administering voxelotor to a patient that has sickle cell disease, wherein the method comprises first discontinuing administration of a strong CYP3A4 inhibitor to avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutically effective amount of voxelotor.

18. Voxelotor for use in a method of administering voxelotor to a patient that has sickle cell disease, wherein the method comprises first discontinuing administration of fluconazole to avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutically effective amount of voxelotor.

19. Voxelotor for use in a method of administering voxelotor to a patient that has sickle cell disease, wherein the method comprises first discontinuing administration of a moderate or strong CYP3A4 inducer to avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutically effective amount of voxelotor.

20. Voxelotor for use in a method of administering voxelotor to a patient that has sickle cell disease, comprising first discontinuing administration of a sensitive CYP3A4 substrate with a narra w the râpe ut ic index to avoid an adverse drug interaction with voxelotor, and then administering to the patient a therapeutically effective amount of voxelotor.

21. Voxelotor for use in a method of concurrently administering voxelotor and a sensitive CYP3A4 substrate with a narrow therapeutic index, wherein the method comprises administering to a patient a therapeutically effective amount of voxelotor and a dosage of a sensitive CYP3A4 substrate with a narrow therapeutic index that is decreased relative to a patient taking a sensitive CYP3A4 substrate with a narrow therapeutic index.

22. Voxelotor for use in a method of concurrent ly administering voxelotor and a strong or moderate CYP3A4 induccr, wherein the method comprises administering to a

15 (i) if co-administration of a sensitive CYP3 A4 substrate with a narrow therapeutic index is unavoidable, decreasing the dose of the sensitive CYP3A4 substrate with a narrow therapeutic index.