Method of treating chemical dependency

Abstract

The present disclosure is directed to a new noribogaine dosing regimen for the treatment of chemical dependency.

Description

ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 METHOD OF TREATING CHEMICAL DEPENDENCY RELATED APPLICATION

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 658,846, filed on June 11, 2024, the content of which is incorporated by reference herein in its entirety for all purposes. FIELD

[0002] The present field of endeavor concerns novel noribogaine dosage regimens and formulations to treat addiction with improved safety margins. Repeated dosing with noribogaine according to methods herein provides effective relief from addiction while controlling QTc interval prolongation.

[0003] Thus, the present disclosure describes a method of treating human subjects with chemical dependency issues, such as addiction to opioids and alcohol, by administering noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof in an improved dosage regimen comprising repeated dosing. The new dosage regimen provides effective treatment for chemical dependency without inducing an unacceptable prolongation of the QTc interval, thereby maintaining the QTmax to within safe limits. BACKGROUND

[0004] Noribogaine, also known as 12-hydroxyibogaine or 12-O-demethylibogaine, is a dominant metabolite of ibogaine found in human, dog, rat, and monkey. Noribogaine has been suggested to have a greater and longer lasting activity in humans than ibogaine for reducing craving for addictive substances and treating chemical dependency. However, like ibogaine, noribogaine administered to humans in high doses can result in unacceptable QT interval prolongation. A prolonged QT interval can predispose a patient to develop torsades de pointes (TdP), a life- threatening arrhythmia. There is no threshold of QTc prolongation at which TdP is certain to occur. A QTc greater than 500 milliseconds (ms) has been associated with a twofold to threefold higher risk for TdP, and each 10 ms increase contributes to approximately a 5% to 7% exponential increase in risk for TdP.

[0005] In controlled clinical studies, noribogaine has been administered to healthy individuals and opioid-dependent patients in ascending single-doses. In one Phase 1 clinical trial, noribogaine was administered to healthy human volunteers at single oral doses of 3 mg, 10 mg, 30 mg and 60ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 mg (see P. Glue et al., The Journal of Clinical Pharmacology, 2015, 55(2), pages 189-194 for a discussion of the trial, which is incorporated by reference herein). In this study, noribogaine was well tolerated. There were no QTcF values greater than 500 ms at any time during treatment. However, one subject dosed with 10 mg noribogaine had a single increase in QTcF of greater than 60 ms at 24 hours post-dosing. Although very low dosing with noribogaine may be relatively safe, human clinical studies demonstrate that such dosing of noribogaine has minimal impact on withdrawal symptoms in addicted patients who are tolerant to opioids. In a second clinical trial, noribogaine was administered at higher single oral doses of 60 mg, 120 mg and 180 mg to opioid- dependent subjects seeking to discontinue methadone opioid substitution therapy (see P. Glue et al., Clinical Pharmacology in Drug Development, 2016, 5(6), pages 460-468 for a discussion of the trial, which is incorporated by reference herein). In this study, noribogaine caused a clear, statistically significant dose- and concentration-dependent effect on the QTc interval, with the largest mean effect of 16ms at 4 hours in the 60 mg group, 28 ms at 3 hours in the 120 mg group and 42 ms at 3 hours in the 180 mg group. In view of these QT effects, particularly at the higher single doses, new noribogaine dosage regimens that are effective to treat chemical dependency with improved safety (e.g. manageable QTc interval prolongation) following administration to human subjects are needed. SUMMARY

[0006] The present disclosure provides a new dosage regimen comprising noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof. The new regimen may be particularly effective to treat subjects with chemical dependency. The new regimen may be administered to human subjects without causing clinically concerning QTc prolongation levels.

[0007] Thus, the present disclosure describes, in one aspect, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof administered to a human subject twice-daily (BID) for up to at least 24 weeks. Depending on the addiction and the severity thereof, the treatment period may be adjusted as appropriate. In severe cases, the treatment period may be longer than 24 weeks, such as 9 months, 12 months or longer. The treatment period may also be less than 24 weeks, such as about 1 to 12 weeks or even 1 to 7 days, and all time periods therebetween.

[0008] In one embodiment of this aspect, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 20 mg. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 10 mg doses. In one particular embodiment, noribogaine or aATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 10 mg oral doses. In one particular embodiment, the time between administering each about 10 mg dose is about 12 hours.

[0009] In one embodiment of this aspect, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 40 mg. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 20 mg doses. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 20 mg oral doses. In one particular embodiment, the time between administering each about 20 mg dose is about 12 hours.

[0010] In one embodiment of this aspect, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 60 mg. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 30 mg doses. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 30 mg oral doses. In one particular embodiment, the time between administering each about 30 mg dose is about 12 hours.

[0011] In one embodiment of this aspect, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 80 mg. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 40 mg doses. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 40 mg oral doses. In one particular embodiment, the time between administering each about 40 mg dose is about 12 hours.

[0012] In the above embodiments, the subject may be conveniently dosed using 10 mg and / or 20 mg unit doses, wherein the weight refers to the equivalent amount of noribogaine free base in the unit dose. However, other unit doses of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof may also be used, such as 15 mg, 25 mg, 30 mg, 35 mg or 40 mg, wherein the weight refers to the equivalent amount of noribogaine free base in the unit dose. The unit doses may conveniently be administered as tablets or capsules.

[0013] The new dosage regimen may be administered to human subjects with chemical dependency to provide a therapeutic reduction in withdrawal symptoms and / or an increase in time to resumption of substance abuse in addicted patients. The therapeutic effect may be achieved whileATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the therapeutic effect may be achieved while maintaining a QT interval prolongation of less than 50 milliseconds. In some embodiments, the therapeutic effect may be achieved while maintaining a QT interval prolongation of less than 30 milliseconds. In some embodiments, the therapeutic effect is achieved while maintaining a QT interval prolongation of less than 20 milliseconds. In some embodiments, the therapeutic effect is achieved while maintaining a QT interval prolongation of less than 10 milliseconds BRIEF DESCRIPTION OF THE FIGURES

[0014] Figure 1 is a flowchart for a randomized, double-blind, sequential-group, multiple-dose, placebo-controlled, Phase 1 dose escalation trial to characterize the pharmacokinetics (PK), pharmacodynamics (PD) and safety of noribogaine in healthy adult participants. DETAILED DESCRIPTION

[0015] It is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of this disclosure will be limited only by the appended claims. The detailed description of the disclosure is divided into various sections only for the reader's convenience and disclosure found in any section may be combined with that in another section. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0016] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0017] The inventors of the present disclosure have identified a new dosage regimen of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof which may effectively treat human subjects with conditions such as chemical dependency, substance abuse and related addictions without causing clinically concerning QTc prolongation levels.

[0018] The new regimen may be particularly effective in treating human subjects with an addiction to opioids.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479

[0019] Alternatively, the new regimen may be particularly effective in treating human subjects with an addiction to alcohol (e.g. alcohol use disorder). Alcohol addiction encompasses the dysregulation of multiple central nervous system pathways involved in executive function leading to excessive consumption of alcohol, despite negative health and social consequences, and withdrawal symptoms when access to alcohol is prevented. Ethanol exerts its toxicity through changes to multiple neurotransmitter systems, including serotonin, dopamine, gamma- aminobutyric acid, glutamate, acetylcholine, and opioid systems. These neurotransmitter imbalances result in dysregulation of brain circuits responsible for reward, motivation, decision making, affect, and the stress response.

[0020] The new regimen comprises administered noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof to a human subject twice-daily (BID) at a daily dose of about 10 mg to about 100 mg. The time between administering the two doses of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof each day may conveniently be about 12 hours.

[0021] The daily dose of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof may be administered to the addicted human subject for up to at least about 24 weeks. Depending on the addiction and the severity thereof, the treatment period may be adjusted as appropriate. In severe cases, the treatment period may be longer than 24 weeks, such as 9 months, 12 months or longer. The treatment period may also be less than 24 weeks, such as about 1 to 12 weeks or even 1 to 7 days, and all time periods therebetween.

[0022] In one embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof may be administered BID at a daily dose of about 10 mg to about 100 mg for 7 days.

[0023] In one embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof may be administered BID at a daily dose of about 10 mg to about 100 mg for 8 days.

[0024] In one embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof may be administered BID at a daily dose of about 10 mg to about 100 mg for 7 days followed by a single dose of one-half the daily dose on day 8.

[0025] Noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof may conveniently be administered to a human subject at a daily dose of about 10 mg to about 100 mg, including a daily dose of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg. In one embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / orATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 ansolvate thereof is administered at a daily dose of about 20 mg to about 80 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 20 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 40 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 60 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered at a daily dose of about 80 mg.

[0026] Noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof may particularly be administered orally (e.g. by tablet or capsule) to a human subject at a daily dose of about 10 mg to about 100 mg, including a daily dose of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg. In one embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered orally (e.g. by tablet or capsule) at a daily dose of about 20 mg to about 80 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered orally (e.g. by tablet or capsule) at a daily dose of about 20 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered orally (e.g. by tablet or capsule) at a daily dose of about 40 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered orally (e.g. by tablet or capsule) at a daily dose of about 60 mg. In one specific embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered orally (e.g. by tablet or capsule) at a daily dose of about 80 mg.

[0027] In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 10 mg oral unit doses. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 10 mg oral unit doses, wherein the time between unit dosing is about 12 hours.

[0028] In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 20 mg oral unit doses. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 20 mg oral unit doses, wherein the time between unit dosing is about 12 hours.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479

[0029] In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 30 mg doses, where each about 30 mg dose consists of one about 10 mg unit dose together with one about 20 mg unit dose. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 30 mg oral doses, where each about 30 mg dose consists of one about 10 mg unit dose together with one about 20 mg unit dose and wherein the time between each about 30 mg dosing is about 12 hours.

[0030] In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 40 mg oral doses, where each about 40 mg dose consists of two about 20 mg unit doses. In one particular embodiment, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is administered daily as two about 40 mg oral doses, wherein the time between each about 40 mg dosing is about 12 hours.

[0031] References herein to specific dosage amounts, including unit dosage amounts, such as 20 mg, 40 mg, 60 mg, 80 mg etc., refer to the actual or calculated weight amount of noribogaine free base in the dosage formulation. It will be appreciated that if a salt of noribogaine, such as noribogaine hydrochloride, is present in the dosage composition, the weight amount of noribogaine hydrochloride present in the dosage formulation will be greater than the specific calculated amount of noribogaine free base quoted.

[0032] In one embodiment, administration of the multiple-dose regimen described herein may provide beneficial human plasma PK results that would not be expected based on results obtained in earlier single-dose noribogaine human trials. In one particular embodiment, the multiple-dose regimen described herein may provide advantageous AUC values. Such AUC values may result in superior CNS target engagement. In one particular embodiment, the multiple-dose regimen described herein may provide Cmax values over the course of treatment that are advantageous. Such Cmax values may result in manageable QT prolongation over the course of treatment.

[0033] In one embodiment, the autonomic functions of the human body adapt to repeat exposure to noribogaine administered according to the multiple-dose regimen described herein. In one particular embodiment, the autonomic functions begin to normalize during the noribogaine treatment period. In one particular embodiment, the QTc-concentration slopes are lower at treatment day 8 than treatment day 1 as the body adapts to repeated exposure to noribogaine.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 Definitions

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings.

[0035] The term "about" when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates, unless otherwise specifically stated or implied herein, approximations which may vary by ( + ) or ( - ) 15%, 10 %, 5 % or 1 %.

[0036] "Administration" refers to introducing an agent into a patient. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used. The agent may be administered by direct blood stream delivery, e.g., sublingual, intranasal, or intrapulmonary administration.

[0037] The related terms and phrases "administering" and "administration of", when used in connection with a compound or pharmaceutical composition (and grammatical equivalents), refer both to direct administration, which may be administered to a patient by a medical professional or by self-administration by the patient, and / or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering the drug to the patient. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.

[0038] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of", when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure. "Consisting of" shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0039] "Noribogaine" refers herein to the compound: as well as pharmaceutically acceptable salts, solvates and / or ansolvates thereof. It should be understood that where "noribogaine" is mentioned herein, one more polymorphs of noribogaine can be utilized and are contemplated.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479

[0040] Noribogaine can be prepared by demethylation of naturally occurring ibogaine which is isolated from Tabernanthe iboga, a shrub of West Africa. Demethylation may be accomplished by conventional techniques such as by reaction with boron tribromide / methylene chloride at room temperature followed by conventional purification. See, for example, Huffman, et al, J. Org. Chem. 50: 1460 (1985), which incorporated herein by reference in its entirety. Noribogaine can also be synthesized as described, for example, in U.S. Patent Publication. Nos. 2013 / 0165647, 2013 / 0303756, and 2012 / 0253037, and PCT Patent Publication No. WO 2013 / 040471, each of which is incorporated herein by reference in its entirety.

[0041] This disclosure is not limited to any particular chemical form of noribogaine, and the drug may be given to patients either as a free base, solvate, ansolvate or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of such acids include, without limitation, those described below as "pharmaceutically acceptable salts" and the like.

[0042] "Pharmaceutically acceptable composition" refers to a composition that is suitable for administration to a human. Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.

[0043] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.

[0044] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g. alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt or solvate of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, theATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art.

[0045] "Treatment," "treating," and "treat" are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate 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 condition but not yet diagnosed as having the condition, (b) impeding the development of the condition, and / or (c) relieving the condition, i.e., causing regression of the condition and / or relieving one or more symptoms of the condition. "Treating" or "treatment of a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to: treating drug dependency; treating, preventing, eliminating, and / or attenuating acute withdrawal symptoms; treating, preventing, and / or attenuating long-term (post-acute) withdrawal symptoms; treating, preventing, eliminating, and / or attenuating cravings; and preventing relapse of drug use.

[0046] "Treating addiction" is defined as a reduction in addictive behavior. This may be determined by a reduction in craving or dependency, such as may be measured in psychological assays or behavioral changes. A behavioral change in addiction may be measured by a reduction in the amount and / or frequency of use of the addictive substance. A period of complete abstinence of use of the addictive drug for at two weeks is strong evidence of treatment. Treatment may also be determined by measuring the level of drugs and metabolites in the patient.

[0047] "Treating addiction" or "treatment of addiction" may also be considered to have at least two separate phases. The first phase is treatment of withdrawal from the drug of addiction, herein known as "withdrawal" or "withdrawing". This is often referred to as acute withdrawal. Withdrawal from drug dependence is characterized by dramatic and traumatic symptoms, including sweating, racing heart, palpitations, muscle tension, tightness in the chest, difficulty breathing, tremor, nausea, vomiting, diarrhea, grand mal seizures, heart attacks, strokes, hallucinations and delirium tremens (DTs). Numerous treatments have been developed in attempts to ameliorate such symptoms. For example, a reduction in the dose of the addictive drug, and / or its replacement with a less addictive or less harmful drug ameliorating the symptoms of withdrawal. Administration of noribogaine is effective in reducing in ameliorating the symptoms of withdrawal. The second phase is treatment of the behavioral aspects of addiction, also referred to as long-term or post-acute withdrawal. Addictive behavior is typically initiated and maintained because, in part, the patientATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 enjoys the experience of drug administration. In addition, long-term changes in the brain may occur due to addiction, and these can increase the likelihood of relapse. Accordingly, relapse is common. In this phase, success may be measured by a combination of factors, such as (i) reduction in craving (ii) increase in the period of abstinence (iii) reduction of "binge" behavior (iv) reduction in the dose of drug taken (v) reduction in harmful behavior. Repeated treatments may be required. Administration of noribogaine is effective in reducing the behavioral aspects of addiction, although repeat treatments may be required. Such repeat treatments may be (a) as-needed intermittent basis or (b) continuous.

[0048] As used herein, the term "patient" refers to humans.

[0049] As used herein, the term "opiate" refers to naturally-occurring alkaloids found in the opium poppy. These include codeine, morphine, oripavine, pseudomorphine, and thebaine. Also included are opium, opium poppy, poppy straw, and extracts and concentrates thereof.

[0050] As used herein, the term "opioid" refers to naturally-occurring opiates and synthetic or semi-synthetic opioids that have psychoactive effects. Non-limiting examples include acetyl-alpha- methylphentanyl, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprodine, anileridine, benzylmorphine, benzethidine, betacetylmethadol, beta- hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diethylthiambutene, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethyl- thiambutene, dioxaphetyl butyrate, diphenoxylate, difenoxin, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levo- alphacetylmethadol, levomethorphan, levorphanol, levophenacylmorphan, levomoramide, lofentanil, loperamide, laudanum, meperidine, meptazinol, metazocine, methadone, 3- methylfentanyl, 3- methylthiofentanyl, metopon, morphine, morpheridine, MPPP (1- methyl-4-phenyl-4- propionoxypiperidine), myrophine, narceine, nicomorphine, noracymethadol, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, para-fluorofentanyl, paregoric, PEPAP (l-(-2-phenethyl)-4-phenyl-4- acetoxypiperidine), pentazocine, phenadoxone, phenampromide, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram,ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 propoxyphene, racemoramide, racemorphan, remifentanil, sufentanil, tapentadol, thiofentanyl, tilidine, tramadol, trimeperidine, mixtures of any of the foregoing, salts of any of the foregoing, derivatives of any of the foregoing, and the like.

[0051] As used herein, the term "QT interval" refers to the measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. Prolongation of the QT interval refers to an increase in the QT interval.

[0052] As used herein, a "patient who has been evaluated for acceptable QT interval prolongation", "patient at low risk for QT interval prolongation" and the like refers to a patient who has been pre-screened by a clinician and determined to have an acceptably low risk for QT interval prolongation. Exemplary criteria for pre-screening are described herein, including history of using drugs that are known to prolong QT interval in at least a subset of patients (e.g., cocaine, methadone, and a number of prescription drugs), personal or familial history of cardiac conditions (including long QT syndrome), and a longer-than- average QT interval. A continuously updated list of medications that are known to cause a prolongation of the QT interval is maintained at www.crediblemeds.org.

[0053] As used herein, “equivalent dose” of a salt or solvate of noribogaine refers to the milligram amount of the salt or solvate the provides the same milligram dose of noribogaine free base. For example, in some embodiments, the disclosure provides for administering the hydrochloride salt of noribogaine (noribogaine HCl). In embodiments, noribogaine hydrochloride is administered a dose that provides 20, 40, 60 or 80 mg of noribogaine. The equivalent dose of noribogaine hydrochloride can be calculated using the molecular weights (mg / mmol) of noribogaine (296.4 mg / mmol) and noribogaine hydrochloride (332.9 mg / mmol).

[0054] In one embodiment of the present disclosure, the patient is prescreened by treatment with a low dose of noribogaine or salt, solvate and / or ansolvate thereof, and the patient's QT interval is evaluated for a period of time to determine whether a therapeutic amount of the drug would result in an unacceptable QT interval in that patient.

[0055] As used herein, the terms "addiction" and "dependence" are used interchangeably to refer to the patient's inability to stop using the drug, even when it would be in his / her best interest to stop.

[0056] The term "solvate" as used herein refers to complexes with solvents in which noribogaine is reacted or from which noribogaine is precipitated or crystallized. For example, a complex with water is known as a "hydrate". Solvates of noribogaine are within the scope of the present disclosure. It will be appreciated by those skilled in organic chemistry that many organicATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 compounds can exist in more than one crystalline form. For example, crystalline form may vary based on the solvate used. Thus, all crystalline forms of noribogaine or a pharmaceutically acceptable solvate thereof are within the scope of the present invention.

[0057] Ansolvates of noribogaine salts are stable and maintain their polymorphic forms during manufacture and storage. They also have a suitable density to allow for facile manufacture of capsules and tablets. Ansolvates characterized by either a crystalline or amorphous structure and their preparation are described in PCT Patent Publication No. WO 2013 / 040471. Pharmaceutical Compositions of the Present Disclosure

[0058] In some embodiments the formulation designed for administration in accordance with the methods provide herein can be suitable for a variety of delivery modes including, without limitation, oral and transdermal delivery. Formulations suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All formulations may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa.1980).

[0059] In a particular embodiment, the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. In certain embodiments, the noribogaine is provided as noribogaine hydrochloride, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine hydrochloride is provided in hard gelatin capsules containing only noribogaine hydrochloride with no excipients.

[0060] Noribogaine can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 Patient Pre-screening and Monitoring

[0061] Without being bound by theory, it is believed that patients who are predisposed to QT interval prolongation are more likely to experience dangerous or life-threatening QT interval prolongation upon treatment with noribogaine or pharmaceutically acceptable salt, solvate or ansolvate thereof. Accordingly, this disclosure is directed to minimizing the risk of an adverse QT interval prolongation in a patient during noribogaine treatment by excluding from treatment any patient having an increased risk factor for an unacceptable QT interval prolongation during the treatment. In one aspect, this disclosure is further directed to pre-screening a patient for a risk factor for an unacceptable QT interval prolongation.

[0062] An "acceptable risk level" in this context indicates that the patient is at low risk of developing QT interval prolongation of greater than 60 milliseconds upon administration of noribogaine or pharmaceutically acceptable salt, solvate or ansolvate thereof. That is, the patient does not have one or more risk factors associated with increased QT interval prolongation. Risk factors associated with increased QT interval prolongation include, without limitation: genetic factors (e.g., pre-disposition to prolonged QT interval); pre-existing condition (e.g., cardiac condition or other condition that makes the patient susceptible to QT interval prolongation and / or causes QT interval prolongation); current or previous use of drugs (prescription or illicit) that are known to have a risk of QT interval prolongation; and previous unacceptable QT response (i.e., greater than 60 milliseconds (ms) prolongation or QT interval over 500 ms) to ibogaine, noribogaine or a pharmaceutically acceptable salt, solvate or ansolvate thereof.

[0063] In one embodiment, patients deemed suitable for such treatment have been evaluated for one or more of the following: genetic / familial risk factors, preexisting conditions, history of using drugs (e.g., prescription or illicit) that are known to have a risk of QT interval prolongation, and / or previous unacceptable QT response to ibogaine, noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof. Preferably, all of such risk factors are included in the evaluation, as well as others deemed appropriate by the attending or pre-screening clinician.

[0064] Pre-screening of patients before treatment with noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof and / or monitoring of patients during noribogaine treatment may be performed to ensure that QT interval is not prolonged beyond a certain value. For example, QT interval greater than about 500 ms can be considered dangerous for individual patients.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479

[0065] In one embodiment, a patient receiving noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof is monitored in a clinical setting. Monitoring may be necessary to ensure the QT interval is not prolonged to an unacceptable degree. A "clinical setting" refers to an in-patient setting (e.g., in-patient clinic, hospital, rehabilitation facility) or an out-patient setting with frequent, regular monitoring (e.g., out-patient clinic that is visited daily to receive dose and monitoring). Monitoring includes monitoring of the QT interval. Methods for monitoring of the QT interval are well-known in the art, for example by ECG. In one embodiment, the patient is monitored after administration of the initial dose. In one embodiment, the patient is further monitored after administration of at least one therapeutic dose. In one embodiment, the patient is monitored for a subset of the treatment, e.g., one day, two days, three days, four days, one week.

[0066] In one aspect, this disclosure is directed to a method for pre-screening a drug-dependent patient prior to administration of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof in order to determine whether the patient has an acceptable risk of QT interval prolongation.

[0067] In one aspect, this disclosure relates to a method for prescreening a drug-dependent patient for safety of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 450 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 420 ms.

[0068] In one aspect, this disclosure relates to a method for prescreening a drug-dependent patient for safety of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a change from baseline in the maximum QT interval over about 50 ms. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a change from baseline in the maximum QT interval over about 40 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a change from baseline in the maximum QT interval over about 30 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a change from baseline in the maximum QT interval over about 20 ms. In one embodiment, prescreeningATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 comprises ascertaining that noribogaine treatment will not result in a change from baseline in the maximum QT interval over about 10 ms.

[0069] In one embodiment, this disclosure relates to monitoring a patient (e.g. via an in-office visit with cardiac monitoring) who is administered a first therapeutic dose of noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof prior to continued dosing on day 2. The determination of prolongation of the dose regimen is within the skill of a qualified clinician.

[0070] Example 1 hereinafter is a Phase 1 clinical trial to evaluate multiple dose pharmacokinetics, pharmacodynamics, safety, and tolerability of ascending doses of noribogaine hydrochloride (administered as capsules) in four cohorts of healthy volunteers. EXAMPLE 1 LIST OF ABBREVIATIONS

[0071] For the purposes of this protocol, 'Investigator' refers to the Principal Investigator or their delegate.Trial Objectives:

[0072] The primary objectives are to determine the pharmacokinetics of noribogaine hydrochloride capsules and to establish a PK / PD relationship of noribogaine concentration on change in QT / QTcI interval. A secondary objective of this trial is to evaluate the safety and tolerability of noribogaine.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 Pharmacokinetic Endpoints:

[0073] Maximum plasma concentration (Cmax: Day 1 & Day 8), time to maximum plasmaconcentration (Tmax: Day 1 & Day 8), trough concentration prior to next dose (C12, C24), areaunder the curve at 12 hours and 24 hours (AUC0-12 hours, AUC0-24 hours: Day 1 & Day 8, and toinfinity (AUC0-infinity), accumulation ratio for AUC, accumulation ratio Cmax, terminalelimination rate constant ( z), half-life (t½), clearance (CL / F) and volume of distribution (Vz / F),whole blood to plasma ratio (1 hour, 2 hours and 6 hours), amount excreted (Ae) (Day 1 & Day 8) and cumulative amount excreted (Cum Ae) (Day 1 & Day 8). Pharmacodynamic Endpoints:

[0074] QT interval corrected for heart rate using individual specific QT interval correction (QTcI) measures (Day 1 & Day 8). Concentration-QTc relationship assessed on placebo-adjustedchange from baseline for QTcI ( QTcI) (Day 1 & Day 8).Safety Endpoints:

[0075] Adverse events will be elicited by asking the participants (prior to any trial rating scales). Any events spontaneously reported by the participant or observed by Investigator's staff (physical examinations) will be recorded. Vital signs, clinical laboratory results and ECG abnormalities will be reported as an adverse event if considered clinically significant. Trial Design:

[0076] Randomized, double-blind, sequential-group, multiple-dose, placebo-controlled, dose escalation trial to characterize the pharmacokinetics (PK), pharmacodynamics (PD) and safety of noribogaine in up to 60 healthy volunteers. Participants will be assigned to one of the four possible cohorts. Each participant will receive noribogaine hydrochloride capsules or placebo twice daily for 8 days (except Day 8, morning only). Each study treatment will be administered with 240 ml water. - Cohort 1: 20 mg noribogaine hydrochloride per day (One 10 mg noribogaine hydrochloride capsule or placebo twice daily) - Cohort 2: 40 mg noribogaine hydrochloride per day (One 20 mg noribogaine hydrochloride capsule or placebo twice daily)ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 - Cohort 3: 60 mg noribogaine hydrochloride per day (One 10 mg noribogaine hydrochloride capsule and one 20 mg noribogaine hydrochloride capsule or placebo twice daily) - Cohort 4: 80 mg noribogaine hydrochloride per day (Two 20 mg noribogaine hydrochloride capsules or placebo twice daily)

[0077] References in the above paragraph to 10, 20, 40, 60 and 80 mg noribogaine hydrochloride refer to the weight of noribogaine free base in the dose administered. Thus, 10, 20, 40, 60 and 80 mg noribogaine hydrochloride correspond respectively to the weight amount of 10, 20, 40, 60 and 80 mg noribogaine free base present in the dose administered.

[0078] The trial consists of three phases: Screening, Treatment Period and Follow-up. Screening can occur up to 35 days before admission. Participants will then stay in the in-patient facility for 13 days to complete the Treatment Period of the trial and will be discharged following completion of the discharge procedures at the end of the period. Participants will return to the facility 2 to 6 days after discharge for the Follow-up procedures. All participants who have given their written informed consent will be screened for eligibility during the Screening window from Day -37 to Day -3 to participate in the trial as per the Schedule of Assessments. Participants must meet all the inclusion criteria and none of the exclusion criteria to be randomized in this protocol. Safety Review:

[0079] Safety review will be conducted after at least 10 subjects have completed each dose cohort. Data will be reviewed after completion of each dose cohort by the SRC to determine progression to the next cohort, in accordance with the SRC Charter. Data Review:

[0080] Data review will include clinical laboratory test results, safety ECG, vital signs and adverse events. Planned Sample Size:

[0081] 4 dose groups with 15 participants per group. 12 subjects will be randomized to noribogaine hydrochloride and 3 will be randomized to placebo.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 Main Criteria for Inclusion in Trial:

[0082] Healthy male and female participants between the ages of 18 to 45 inclusive, with BMI 18 - 30 kg / m2with normal ECG findings, i.e. QTcF interval 450 ms and normal morphology that would permit accurate assessment of the QT interval. Participants must agree to use highly effective methods of contraception. Detailed Trial Inclusion / Exclusion Criteria: Inclusion Criteria - Male or female aged 18 - 45 years (inclusive) at the time of signing the ICF at Screening - Participants who are healthy as determined by medical evaluation, including no clinically significant relevant abnormalities as determined by medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory evaluation that is likely to interfere with participation in, or ability to complete the study, or to potentially confound interpretation of study results, as assessed by the Investigator - Non- or ex-smoker (an ex-smoker is defined as someone who completely stopped using nicotine, nicotine cessation products / medications, or tobacco containing products [e.g., gum, lozenges, patches, vaporizers, smokeless tobacco] for at least 30 days prior to the first IMP administration) - Body Mass Index (BMI) of 18 - 30 kg / m2(inclusive) at Screening - Systolic blood pressure: 140 mmHg and 90 mmHg - Diastolic blood pressure: 90 mmHg and 55 mmHg - Heart rate: 90 beats per minute (bpm) and 55 bpm - Normal ECG with QTcF interval 450 ms and normal morphology that would permit accurate assessment of QT assessment in the opinion of the Investigator at Screening and Admission - Ability to provide written, personally signed, and dated informed consent in accordance with the ICH GCP Guidelines E6 (R2) (2016) and applicable regulations, before any study-specific procedures are performed - Participants must be willing to adhere to highly effective methods of contraception - Male participants who agree not to donate sperm during this trial until 90 days after the last doseATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 - Female participants who agree not to donate ova from enrolment, during the trial, until 90 days after the last dose of trial drug - Participants must agree to take measures, such as use of sunscreen and wearing of hats and long-sleeve garments, to minimize exposure to UV light for the duration of study treatment and for 10 days after the last dosage Exclusion Criteria: - History of, or concurrent clinically significant, cardiovascular conditions, including but not limited to arrhythmia-related cardiac events, cardiomyopathy, syncope, long QT syndrome, cardiac channelopathies, orthostatic hypotension and structural cardiac anomalies; dysautonomia; gastrointestinal; renal; hepatic; neurologic; hematologic; endocrine; oncologic; pulmonary; immunologic or psychiatric conditions; or any other condition which, in the opinion of the Investigator, would jeopardize the safety of the participant or impact the validity of the study - Family history in first degree relatives for unknown and / or known arrhythmia-related cardiac events, cardiomyopathy, syncope, long QT syndrome, Brugada's syndrome, sudden death attributed to cardiac causes, and familial cardiac channelopathies - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with interpretation of QTc interval changes. This includes participants with any of the following at Screening or Admission: • Sinus node dysfunction • Clinically significant PR interval prolongation • Intermittent second or third-degree AV block • Incomplete or complete bundle branch block (QRS >110ms) • Sustained cardiac arrhythmias including (but not limited to) atrial fibrillation, supraventricular or ventricular tachycardia, any symptomatic arrhythmia except for isolated ventricular systoles. • Undue ectopic burden • Abnormal T wave morphology - History of seizures or seizure disorder or convulsions - History of any clinically significant neurological or psychiatric conditions, as determined by the Investigator - History of any clinically significant disorders that may affect drug absorptionATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 - Participant has had significant traumatic injury, major surgery or open biopsy within 30 days prior to study Screening - Previous or current alcohol, or other drug dependence (excluding nicotine and caffeine), based on medical history - Any history of suicidality based upon clinical history, source documents, or scores on the Columbia-Suicide Severity Rating Scale (C-SSRS) - Participants who (for whatever reason) have been on an abnormal diet (such as one that severely restricts specific basic food groups [e.g., ketogenic diet], limits calories [e.g., fast], and / or requires the use of daily supplements as a substitute for the foods typically eaten at mealtimes), during the 30 days preceding Screening - Participants who are unable to adhere to a standard diet as provided in the unit for the duration of the inpatient stay - Concurrent medical conditions requiring use of prescription medication within 30 days (or 5 elimination half-lives, whichever is longer) of Screening - Intake of non-prescription medications, including vitamins, herbal products or dietary supplements within 14 days of Screening, with the exception of contraceptives and limited paracetamol - Intake of experimental agents within at least 90 days (or a period equivalent to 5 half- lives of the agent, whichever is longer) prior to Screening - Clinically significant concurrent medical conditions considered by the Investigator, determined by medical history, physical examination, vital signs and 12 lead-ECG - Clinically significant clinical laboratory assessments (serum chemistry, haematology, and coagulation) at Screening and / or Admission (D-2) that are not within normal limits and deemed unacceptable by the investigator. Repeat testing is permitted at the discretion of the investigator to determine significance. Ethnically adjusted ranges will permitted - Postural increase in heart rate > 30 bpm on Screening and Admission (D-2) - QTcF interval > 450 ms following 1 minute and / or 4 minute recovery from exercise stress test - Positive test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or Human Immunodeficiency Virus antibody (HIV Ab) at Screening - Participants with history, or evidence of substance / alcohol abuse - Participants with history, or evidence of inhalant abuseATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 - Positive urine drug test for alcohol, opioids, cocaine, amphetamine / methamphetamine, benzodiazepines, tetrahydrocannabinol (THC), barbiturates, or methadone at Screening or Admission - Positive urine screen for infection or cotinine at Screening or Admission (smoking and the use of tobacco products is not permitted for 30 days prior to the first dose of trial drug and throughout the duration of the trial) - Positive COVID test at Admission - Donation or significant blood loss or blood products of 500 mL or more within 56 days prior to Screening or donation or loss of plasma within seven days prior to Screening - Women who are pregnant (including a positive pregnancy test at Screening and D-2), planning a pregnancy or breastfeeding - Participants with a known allergy to noribogaine, ibogaine or any of the excipients - Participants who will not abstain from engaging in strenuous exercise during the throughout the trial (up until the follow up visit) - Participants who will not abstain from ingesting alcohol, drinks containing xanthine >500mg / day (eg. Coca Cola®, coffee, tea, etc.), 72 hours before initial dosing and throughout the duration of the trial - Participants who will not abstain from consuming any other substances known to be potent inhibitors or inducers of CYP P450s. This includes food or drink products containing cranberry, pomegranate, star fruit, grapefruit, pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from these fruits) for 21 days before initial dosing and throughout the duration of the trial - Participants who are deemed unlikely to be able to comply with the requirements of the protocol - Participants with a known intolerance to continuous ECG lead adhesive exposure considered clinically significant by the Investigator - Dosed in a previous cohort for this clinical trial - Participants with veins unsuitable for venous access via venepuncture or cannulation, as determined by the trial site staff Treatment Duration:

[0083] Screening can occur up to 35 days before admission. The in-patient stay is 13 days, during which the treatment will be administered. Treatment will be administered for 8 days, withATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 the participants returning to the trial site 2 to 6 days after discharge for follow-up procedures. The total participant duration is up to 54 days to complete the entire trial. Primary and Secondary Outcome Measures: ECG Analysis

[0084] Intensive cardiac assessments will be performed using food effects on the ECG to establish assay sensitivity. Analysis of drug related QT / QTc interval changes relative to plasma PK concentrations will be conducted on all dose regimens. Concentration-QTc Analysis

[0085] The primary endpoint is defined as the concentration-QTc-model based QTc placebocorrected differences from baseline ( QTc), where baseline is the average of the 3 pre-dosemeasurements of Day 1. ECGs from Day 1 and Day 8 will be used for comparison against baseline. More specifically, a linear mixed effect model relating the change from baseline to the concentration of noribogaine will be fitted. Apart from the concentration, the model will include fixed effects for time and treatment ("treatment intercept" with levels active and placebo) and baseline as a covariate. Random effects per subject for the intercept and, if feasible, for the concentration will be included. More specifically, if the model does not converge even after rescaling of the covariates, the random effects for concentration will be removed. If convergence is still not given, the covariance structure may be simplified. If the treatment intercept differssignificantly from nought, a nonlinear e-max model maybe investigated. Predictions of the effectof noribogaine at the concentrations seen at Tmaxwill be usedto exclude an effect of regulatoryconcern (i.e., a one-sided 95% confidence interval for QTc completely below 10 ms). Diagnostic plots include the presentation of observed vs. predicted values and the plot of the residuals against the variables in the model as well as against day.

[0086] The observed QTc versus concentration will be presented. In addition, a decile plot will be presented with the partial residual with respect to concentration as dependent and concentration as independent variable. Pharmacokinetics (PK)

[0087] Non-compartmental analysis will be used for estimation of pharmacokinetic parameters. The following pharmacokinetic parameters shown in Table 1 will be calculated for noribogaine.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 Table 1 - PK ParametersATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479

[0088] The individual plasma concentration data, and the actual time for noribogaine administration and blood sampling will be used in the derivation of the PK parameters.

[0089] AUC0-t and AUC0-inf will be calculated using the linear / log trapezoidal method, applying the linear trapezoidal rule up to Cmax and the log trapezoidal rule for the remainder of the curve. EXAMPLE 2

[0090] This study compared the QT interval for an equivalent 60 mg daily dose of noribogaine across the single dose and multi-dose studies. For multiple dose study, steady state values at day 8 were measured.

[0091] For the noribogaine HCl salt single dose study using 60 mg in healthy volunteers, the results are provided in Table 2. Table 2: Results of the Single Dose Study

[0092] For the noribogaine HCl salt multi-dose study with 30 mg administered twice daily in healthy volunteers, the results are provided in Table 3. Reported data relates to steady state reached for 30 mg twice daily.ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 Table 3: Results of the Multi Dose Study

[0093] This study shows that the QTcF drops from 32.8 msec in the single dose study using 60 mg in healthy volunteers to 10 msec in the multi-dose study 30 mg twice daily in healthy volunteers. Notably, noribogaine concentration was similar for the single dose study and multi- dose study at steady state.

Claims

ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 CLAIMS 1. A method of treating a human subject with chemical dependency, the method comprising administering noribogaine or a pharmaceutically acceptable salt, solvate and / or ansolvate thereof to the human subject twice-daily (BID) at a daily dose of about 10 mg to about 100 mg.

2. A method of treating a human subject with an addiction to alcohol (e.g. alcohol use disorder), the method comprising administering to the human subject twice-daily (BID) at a daily dose of about 10 mg to about 100 mg noribogaine, or an equivalent dose of a pharmaceutically acceptable salt, solvate and / or ansolvate thereof.

3. The method of claim 1 or claim 2, wherein the treatment period is up to at least about 24 weeks.

4. The method of any one of claims 1-3, wherein the daily dose is about 20 mg noribogaine or an equivalent dose of pharmaceutically acceptable salt, solvate and / or ansolvate thereof.

5. The method of claim 4, comprising administering noribogaine hydrochloride at a dose equivalent 20 mg noribogaine ((i.e., about 22.5 mg noribogaine hydrochloride).

6. The method of any one of claims 1-3, wherein the daily dose is about 40 mg noribogaine or an equivalent dose of pharmaceutically acceptable salt, solvate and / or ansolvate thereof.

7. The method of claim 6, comprising administering noribogaine hydrochloride at a dose equivalent to 40 mg noribogaine (i.e., 44.9 mg noribogaine hydrochloride).

8. The method of any one of claims 1-3, wherein the daily dose is about 60 mg noribogaine or an equivalent dose of a pharmaceutically acceptable salt, solvate and / or ansolvate thereof.

9. The method of claim 8, comprising administering noribogaine hydrochloride at a dose equivalent to 60 mg noribogaine (i.e., about 67.4 mg noribogaine hydrochloride).ATTORNEY DOCKET NO.: DEMX-067 / 01WO 342446-2479 10. The method of any one of claims 1-3, wherein the daily dose is about 80 mg noribogaine or an equivalent dose of a pharmaceutically acceptable salt, solvate and / or ansolvate thereof.

11. The method of claim 10, comprising administering noribogaine hydrochloride at a dose equivalent to 80 mg noribogaine (i.e., 89.9 mg noribogaine hydrochloride ).

12. The method of any one of claims 1-11, wherein the two doses of the daily dose are administered to the human subject about 12 hours apart.

13. The method of any one of claims 1-12, wherein the therapeutic effect is achieved while maintaining a QT interval of less than about 500 milliseconds during said treatment.

14. The method of any one of claims 1-12, wherein the therapeutic effect is achieved while maintaining a QT interval prolongation of less than 50 milliseconds or less than 30 milliseconds or less than 20 milliseconds or less than 10 milliseconds.

15. The method of any one of claims 1-14, wherein noribogaine hydrochloride is administered orally to the human subject.

16. The method of any one of claims 1-14, wherein noribogaine hydrochloride is administered orally to the human subject as capsules.

17. The method of any one of claims 1-16, wherein the exposure levels of noribogaine provide enhanced CNS target engagement.

18. The method of any one of claims 1-17, wherein the autonomic functions of the human body adapt to noribogaine repeat dosing and normalize during the noribogaine treatment period.

19. The method of claim 18, wherein the QTc-concentration slopes are lower at the end of the noribogaine treatment period than the first day of the noribogaine treatment period.

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