U.S. Department of Justice Drug Enforcement Administration

Schedule of Controlled Substances: Placement of Serdexmethylphenidate into Schedule IV

Background, Data, and Analysis: Eight Factors Determinative of Control and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by

Diversion Control Division, Drug and Chemical Evaluation Section Washington, D.C. 20537

April 2021

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I. Background

Serdexmethylphenidate chloride (SDX), chemically known as 3-[[[(1S)-1-carboxy-2- hydroxyethyl]-amino]carbonyl]-1-[[[[(2R)-2-[(1R)-2-methoxy-2-oxo-1-phenylethyl]-1- piperidinyl]carbonyl]oxy]methyl]pyridinium chloride, is a new molecular entity with no central nervous system (CNS) activity. It is metabolized in the large intestine to (d- MPH), a schedule II CNS . Thus, SDX is considered a prodrug of d-MPH.

On March 2, 2020, Commave Therapeutics S.A. (Sponsor), in partnership with KemPharm, Inc., submitted to the U.S. Food and Drug Administration (FDA) a new drug application (NDA) for a combination drug product containing SDX and d-MPH, proposed as a treatment for Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years of age and older (HHS review, 2021). On March 02, 2021, FDA approved the NDA for AZSTARYS, a combination drug product containing d-MPH and SDX. According to the FDA-approved product label, AZSTARYS capsules contain 28/6, 42/9 or 56/12 mg of serdexmethylphenidate chloride/dexmethylphenidate hydrochloride (equivalent to 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, and 52.3 mg/10.4 mg of serdexmethylphenidate/dexmethylphenidate, respectively)1.

The Drug Enforcement Administration (DEA) received, on March 2, 2021, from the Department of Health and Human Services (HHS), a scientific and medical evaluation entitled “Basis for the Recommendation to Control Serdexmethylphenidate and its Salts in schedule IV of the Controlled Substances Act” and a scheduling recommendation (HHS review, 2021). Following consideration of the eight factors and findings related to the substance’s abuse potential, legitimate medical use, and dependence liability, HHS2 recommended that SDX and its salts be controlled in schedule IV of the Controlled Substances Act (CSA) under 21 U.S.C. 812(b). According to the HHS review, SDX has not been marketed in any country for any medical indication.

The CSA requires DEA, as delegated by the Attorney General3, to determine whether HHS’s scientific and medical evaluation, HHS’s scheduling recommendation, and all other relevant data constitute substantial evidence that a substance should be scheduled. 21 U.S.C. 811(b). This document is a summarized review of the relevant data, law enforcement information, and determination to control SDX under the CSA.

II. Eight Factors Determinative of Control

Pursuant to 21 U.S.C. 811(c), DEA must consider eight factors in making any finding of substantial evidence of potential for abuse, including the data and law enforcement information relevant thereto.

Factor 1. SDX’s Actual or Relative Potential for Abuse

1 https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212994s000lbl.pdf. 2 Administrative responsibilities for evaluating a substance for control under the CSA are performed for HHS by FDA, with the concurrence of the National Institute on Drug Abuse (NIDA), according to a Memorandum of Understanding (50 FR 9518; March 8, 1985). 3 28 CFR 0.100(b). 2

As stated by HHS, SDX is a new drug that has not been marketed in the United States, or any other country. As such, information on the actual abuse of SDX is not available. The term “abuse” is not defined in the CSA. However, the legislative history of the CSA4 suggests using the following four prongs in determining whether a particular drug or substance has a potential for abuse:

a) There is evidence that individuals are taking the drug or other substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community; or

According to HHS, SDX has not been marketed legally in the United States or in any other country. FDA is not aware of its availability outside the legal channels either in the United States or in any other country. This characteristic of abuse is not applicable (HHS review, 2021). To date there have been no published reports regarding evidence that individuals are taking SDX in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community.

b) There is significant diversion of the drug or other substance from legitimate drug channels; or

HHS states that SDX is not currently marketed legally, or to their knowledge illegally, in the United States or any other country that they are aware of and there are no known legitimate drug channels from which it can be diverted. Thus, this characteristic of abuse potential is limited as well. DEA notes that there are no reports of law enforcement encounters of SDX in the National Forensic Laboratory Information System (NFLIS)5 database.

c) Individuals are taking the drug or substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs; or

According to HHS, SDX is currently not yet available or marketed in the United States, or any country that HHS is aware of and therefore, there is limited information to assess this characteristic of abuse potential (HHS review, 2021). To date there have been no published reports regarding evidence that individuals are taking SDX on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer SDX.

d) The drug is a new drug so related in its action to a drug or other substance already listed as having a potential for abuse to make it likely that the drug substance will have the same potential for abuse as such drugs, thus making it reasonable to assume that there may be significant diversion from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

As mentioned in the HHS review and discussed more fully in Factor 2, clinical studies show that SDX produces effects that are similar to other stimulant drugs in schedule IV, such as

4 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970) reprinted in U.S.C.C.A.N. 4566, 4603. 5 The National Forensic Laboratory Information System (NFLIS) is a national forensic laboratory reporting system that systematically collects results from drug chemistry analyses conducted by State and local forensic laboratories in the United States. NFLIS data were queried on March 4, 2021. 3

phentermine. The pharmacological mechanism of action of SDX is based on its prodrug characteristics, as it must be metabolized to d-MPH to exert its effects. According to HHS, the capacity of orally administered SDX to produce abuse related effects is similar to that of schedule IV stimulant drugs such as phentermine. SDX as compared to d-MPH in clinical studies demonstrated a lower potential for abuse when taken by the intranasal (IN) or intravenous (IV) routes.

Data gathered from in vitro binding studies show that SDX does not interact with or transporters, the primary site of action of d-MPH or with any receptor system known to be a site of action for abuse related effects. Data from in vitro chemical studies demonstrated that under certain experimental conditions, SDX was converted to a pharmacologically inactive metabolite, ritalinic acid. However, SDX was stable in most acidic and basic experimental conditions. SDX is also stable in human plasma, whole blood, stimulated intestinal and gastric fluid, and in human kidney, liver, intestinal and lung S9 fractions as noted in Factor 3.

Because SDX is a new molecular entity and not available or marketed in the United States, evidence to date regarding its diversion, illicit manufacturing, or deliberate ingestion is currently lacking. However, as HHS notes (HHS review, 2021), pharmacological data indicates that SDX has a lower abuse potential than its metabolite, d-MPH, a schedule II drug. Data also indicate that SDX is likely to have abuse potential similar to schedule IV such as phentermine, when taken at supratherapeutic doses by oral route. Thus, it is reasonable to assume that there will be equivalent diversions from legitimate channels of SDX, use contrary to or without medical advice, and a lower capability of creating hazards to users and to the safety of the community.

Factor 2. Scientific Evidence of SDX’s Pharmacological Effects

According to the HHS review, the pharmacology of SDX may be similar to some stimulant drugs but only via its metabolism in the large intestine to d-MPH. SDX has no CNS activity and is a prodrug of d-MPH (HHS review, 2021).

In Vitro Receptor Binding Studies

As described in the HHS review, there were two in vitro receptor binding studies conducted by the Sponsor, Study AB54825 and Study AB54826. The first study (Study AB54825) provided the binding profile of SDX at the dopamine (DAT), norepinephrine (NET), and (SERT) transporters. The second study (Study AB54826) was used to identify binding to any other receptors known to interact with drugs of abuse (HHS review, 2021).

In the first study, the binding affinities of SDX were determined at the DAT, NET, and SERT transporters. The binding affinity at the DAT transporter was determined using CHO-S cells expressing human DAT transporters using [125I]-RTI-55 as the radioligand and in the presence of 10 μM nomifensine to estimate non-specific binding as well as a reference control, GBR-12909. The binding affinity at the NET transporter was determined in dog kidney MDCK cells expressing human NET transporters, using [125I]-RTI-55 as the radioligand and in the presence of 10 μM as a reference control and to estimate non-specific binding. Lastly, binding to the SERT human transporter was measured in HEK-293 cells expressing human SERT transporter, using [3H]-Paroxetine as the radioligand, 10 μM to estimate non-specific binding, and fluoxetine as the reference control. SDX was tested at six

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concentrations, ranging from 0.03 to 10 μM and IC50 values were determined for SDX and the 6 reference controls. The IC50 values for SDX were all greater than 10 μM indicating that there was no significant binding of SDX to any of the monoaminergic transporters. The IC50 values for all references controls were within the historical IC50 range. This study indicates that unlike d-MPH, SDX does not interact with DAT and NET monoamine transporters.

The Sponsor conducted a second study to test binding affinities of SDX for other receptor systems, ion-gated channels, and transporters included in a 68 molecular target screening panel. This study used a concentration of 10 μM SDX and defined a significant response as ≥ 50% binding inhibition. Results demonstrated that SDX did not bind to any of the molecular targets tested.

Results from the above mentioned studies demonstrate that: (1) SDX does not interact with DAT and NET transporters, which are the primary site of action of racemic MPH and d- MPH (a schedule II drug). (2) SDX does not have affinity for any other receptors systems associated with drugs of abuse. (3) SDX is likely pharmacologically active only as it is metabolized to d-MPH.

Central Nervous System Effects

Animal Behavioral Effects

HHS cites a study by the Sponsor evaluating SDX’s effect on general behavior conducted in male and female Sprague-Dawley rats. SDX was tested at doses of 12.5, 25, and 50 mg/kg (orally), along with d-MPH at 25 mg/kg dose as a positive control, and a vehicle arm. Pharmacological and toxicological signs in rats were observed at 15, 30, and 45 minutes and 1, 2, 3, 4, and 24 hours following oral administration. Recorded data and observations included body temperature, pupil size, startle responses increased salivation and /or tearing, abdominal tone, and loss of righting reflex as well as various CNS effects (e.g., seizures/convulsions, body tremors, ataxia, abnormal posture, excretion, awareness reaction, motor activity, piloerection, stereotypy, decreased respiration, vocalization, and irritability).

Results indicated that the vehicle control, and the two lower doses of SDX (12 and 25 mg/kg) did not produce any CNS effects up to 24 hours post-dose observational period. The highest dose of SDX (50 mg/kg) increased CNS activity at 45 minutes post-dose and lasted up to 3 hours. Dilated pupils were also observed from 45 minutes up to 4 hours after dosing. The positive control (d-MPH) increased activity as well as pupil size at 45 minutes after dosing and lasted for 3 to 4 hours. SDX (50 mg/kg) or d-MPH (25 mg/kg) did not affect body temperatures (HHS Review, 2021).

In conclusion, as mentioned by HHS, this observational behavioral study demonstrated that SDX at the highest dose (50 mg/kg) tested showed some signs of stimulant activity in rats.

6 In binding studies, IC50 represents the concentration of the ligand (test substance) that displaces 50% of the specific radioligand selected to label the receptors. 5

Human Behavioral Effects

As noted by HHS, human behavioral effects from SDX administration were obtained from human abuse potential (HAP) studies and from adverse events data reported in clinical efficacy studies.

Human Abuse Potential Studies for NDA 212994 (Studies KP415.A01, KP415.A03, and KP415.A02)

As stated by HHS, data from HAP studies help determine whether a test drug produces positive subjective effects in participants in comparison to a known drug of abuse and placebo. Participants in these studies have a history of recreational drug use, but are not drug dependent. A test drug is likely to have abuse potential when the test drug produces consistently high response on scales such as “Drug Liking,” “Good Drug Effects,” and “High” that are significantly different from placebo (HHS Review, 2021).

HHS described three HAP studies that evaluated the abuse potential of SDX by oral, intranasal (IN) and intravenous (IV) routes. The oral route of administration is the most common for abuse of stimulants, however, in people with substance use disorders, the IN and IV routes may be used to obtain greater reinforcing effects.

Oral HAP study KP415.A01: According to HHS, a HAP study was conducted in healthy non-dependent recreational stimulant abusers to evaluate the abuse potential and pharmacokinetics of oral SDX as compared to Focalin XR (d-MPH HCL, a schedule II drug), phentermine (a schedule IV drug) and placebo in a double-blind, randomized, single-dose, active-and placebo-controlled, five-treatment, crossover study. Focalin XR and phentermine are known to have stimulant activity and thus were used as the active comparators. The doses of the active comparators were at twice the maximum daily oral dose, with Focalin XR (extended- release d-MPH), as the primary positive control, administered as an 80 mg dose, and phentermine as the secondary positive control, administered as a 60 mg dose. The doses of SDX, 120 mg and 240 mg, represented one and two times the highest estimated therapeutic dose of KP484, a single ingredient SDX capsule. The maximum single dose of SDX in the combination product (SDX/d-MPH) is 56 mg (HHS Review, 2021).

As stated in the HHS review, prior to the treatment phase, subjects participated in a drug discrimination test to determine if subjects could differentiate between effects of a single dose of Focalin XR versus placebo administered orally. Participants that successfully completed the drug discrimination phase was entered into the main part of the study, treatment phase (HHS Review, 2021).

As mentioned by HHS, pharmacodynamic assessments of the reinforcing effects of SDX were made using unipolar or bipolar visual analog scales. The unipolar visual analog scale (VAS) were presented using points 0 to 100 where a rating such as “Not At All”, scored 0 and “Extremely”, scored 100, with the neutral point equaling 0 (High VAS). Bipolar VASs also used a 0 to 100 point scale, where the neutral point equaled 50 (Drug Liking, Overall Drug Liking (ODL), Take Drug Again [TDA]), and the neutral point was labeled with a rating, such as “neither like nor dislike.” The endpoint of maximum (peak) effect (Emax) for Drug Liking (“at

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this moment”), was chosen as the primary endpoint. Secondary endpoints assessed 12 and 24 hours post dose, were the Emax for ODL VAS (“Overall, my liking for this drug is”) and the Emax for TDA VAS (“I would take this drug again”). Exploratory endpoints included the Emax for Feeling High (“At this moment, I feel high”) (HHS Review, 2021).

HHS states that the study results were based on 45 subjects that completed all treatment periods. The study was validated by demonstrating that the primary analysis showed that 80 mg Focalin XR produced a mean response (80.4) on the Drug Liking Emax that was significantly larger than placebo (55.4). Both doses of SDX (120 and 240 mg) produced mean responses (62.2 and 63.7, respectively) that were significantly less (p ≤ 0.0058) than 80 mg Focalin XR (80.4). The lower dose of SDX (120 mg) produced a mean response (62.2) that was significantly less (p = 0.0195) than 60 mg phentermine (77.7); however, the higher dose of SDX (240 mg) did not produce a mean response that was significantly less than the 60 mg dose of phentermine (p = 0.0664). Both doses of SDX had abuse potential based on the comparison to placebo. The median time to maximum responses (TEmax) in Drug Liking for the two active comparators (phentermine and Focalin XR) was approximately 2 hours, whereas the TEmax for SDX occurred at approximately 3 hours.

Similar scores for the secondary endpoints, ODL and TDA (measured at 12 and 24 hours post-doing) were observed for both doses of SDX compared to Focalin XR (80 mg), which was inconsistent with findings from the primary analysis. HHS states that this inconsistency could be contributed to the Drug Disliking and Bad Effects measures observed after 10 hours of Focalin XR dosing. Furthermore, SDX had lower scores for OLD and TDA compared to phentermine (60 mg). The results of the High Emax demonstrated that both doses of SDX was significantly greater than placebo, however, both active comparators produced significantly greater mean responses than both SDX and placebo (HHS Review, 2021).

As summarized by HHS, the KP415.A01 oral study demonstrated that the primary endpoint and exploratory endpoints were consistent with SDX having a lower abuse potential than Focalin XR, a schedule II drug, even though the secondary endpoints did not show a difference. SDX at oral doses of 120 mg and 240 mg did show a lower or similar abuse potential as phentermine, a schedule IV drug, on all endpoints. However, based on the comparison to placebo, this study did not demonstrate an absence of abuse potential for either dose of SDX (HHS Review, 2021).

Intravenous HAP Study KP415.A03: As HHS notes, this study was conducted to assess the HAP and pharmacokinetics of SDX compared to d-MPH after intravenous administration. Solutions of the active pharmaceutical ingredients (APIs) were chosen rather than from the manipulated drug product formulations containing the APIs for this study. This eliminates the unethical administration of any excipients present in those drug product formulations (HHS Review, 2021).

According to HHS, this HAP study enrolled healthy, nondependent individuals with a history of recreational stimulant use via non-oral routes of administration. There were two parts to this study, Part A, the dose selection phase and Part B, the treatment phase. The first phase was implemented to ensure that an optimal dose level was selected since limited knowledge is available regarding the safety and pharmacodynamic effects of d-MPH when administered

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intravenously. The treatment phase was based on tolerability and HAP pharmacodynamic assessments (HHS Review, 2021).

HHS states that the design of the dose selection phase was a within-subject single ascending dose study with pre-specified stopping rules. A dose of 15 mg d-MPH API was selected for Part B based on the results from study Part A. The treatment phase was a randomized, double-blind, placebo- and active-controlled, crossover study to evaluate the abuse potential of SDX as compared with d-MPH after IV administration.

Similar to the oral dose study, subjects participated in a drug discrimination test to determine if subjects could differentiate between effects of a single dose of d-MPH API versus placebo administered by intravenous injection. Participants that successfully completed the drug discrimination phase were entered into the treatment phase (30 subjects) and administered via intravenous injection, the following treatments labeled A through C (HHS Review, 2021):

• Treatment A: 30 mg SDX API (molar equivalent to d-MPH relative to the 15 mg d- MPH API control; see Factor 3) • Treatment B: 15 mg d-MPH API (active control) • Treatment C: Matching placebo

As HHS notes, Drug Liking VAS Emax was the primary endpoint in the treatment phase. The key secondary endpoint was the TDA VAS Emax and other secondary endpoints included the ODL VAS Emax and the Feeling High VAS Emax. Validation of the study was confirmed when the active comparator, 15 mg d-MPH API, demonstrated a significantly greater mean for Drug Liking Emax than placebo. The results of SDX API (30 mg) on the measure of mean Drug Liking Emax (56.6) was significantly less than that of 15 mg d-MPH API (84.3) (p < 0.0001). The difference in means between 30 mg SDX API and placebo (53.8) was not significant. For the measure of TDA Emax, the active control (15 mg d-MPH API) was significantly greater than SDX API. The difference in mean between 30 mg SDX API and placebo was significant. HHS notes that the other secondary endpoints (ODL VAS Emax and the Feeling High VAS Emax) supported the findings from the primary analysis (HHS Review, 2021).

As summarized by HHS, the HAP IV study demonstrated that IV administration of 30 mg SDX API had less abuse potential than 15 mg d-MPH API. This result is consistent with the pharmacodynamic results discussed in Factor 3, which showed a lack of conversion of SDX to d- MPH in blood following IV administration. Based on the comparison to placebo, this study demonstrated that SDX did not have abuse potential compared to placebo (HHS Review, 2021).

Intranasal HAP Study KP415.A02: As HHS notes, this study was a randomized, double- blind, single-dose, active-and placebo-controlled evaluation conducted to assess the HAP and pharmacokinetics of 80 mg SDX API compared to 40 mg d-MPH API and placebo after IN administration. The study used 45 healthy, nondependent individuals with a history of recreational stimulant use and experience with IN insufflation of stimulants (HHS Review, 2021).

A pilot study (KP415.DR1) was first conducted in healthy, nondependent individuals with a history of recreational CNS stimulant use to determine a dose of d-MPH that produced

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significant positive psychostimulant effects (e.g., Drug Liking, etc.) while minimizing potential adverse effects. This optimal dose of d-MPH was used as the positive control in Study KP415.A02. Single IN doses of 20, 40, and 60 mg d-MPH were used in the pilot study and results indicated that a 40 mg IN dose of d-MPH API was the optimal dose. An 80 mg dose was then selected for the IN dose of SDX API in Study KP415.A02 based on the molar equivalence to the selected d-MPH API dose (HHS Review, 2021).

As stated in the HHS Review, and similar to the other two studies, Drug Liking VAS Emax was the primary endpoint in the treatment phase. The secondary endpoints were the TDA VAS Emax and the ODL VAS Emax. Exploratory endpoints included the Emax for High and Ease of Nasal Insufflation VASs. Validation of the study was confirmed when the active comparator, 40 mg d-MPH API, demonstrated a significantly greater mean for Drug Liking Emax than placebo (HHS Review, 2021).

The effect of SDX API (80 mg) on the measure of mean Drug Liking Emax (71) was significantly less than that of 40 mg d-MPH API (93.2) (p<0.0001). However, 80 mg SDX API produced a mean Drug Liking Emax value that was significantly greater than placebo (51.1). Similarly, the mean ODL Emax and the TDA Emax values were significantly less for 80 mg SDX API than that of 40 mg d-MPH API. The difference in means between 80 mg SDX API and placebo was significant. The results on the exploratory endpoint, High Emax were consistent with the findings on the primary and key secondary endpoints. At five minutes post- dose for SDX API, Ease of Nasal Insufflation VAS scores were markedly higher than for d-MPH API and placebo, suggesting greater difficulty in snorting SDX. However, all subjects were able to completely insufflate all treatments (HHS Review, 2021).

As summarized by HHS, the IN HAP study demonstrated that IN administration of 80 mg SDX API had less abuse potential than 40 mg d-MPH API, but greater than that of placebo. This result is consistent with the pharmacodynamic results discussed in Factor 3, which showed limited conversion of SDX to d-MPH in the nasal mucosa following IN administration (HHS Review, 2021).

Adverse Events in All Clinical Safety and Efficacy Studies Conducted with Serdexmethylphenidate for NDA 212994

Phase 1 and HAP studies

According to HHS, 76 healthy volunteers participated in five Phase 1 studies to evaluate SDX without an active control (i.e. d-MPH). The adverse events profile was analyzed by FDA where they reviewed the frequency of abuse-related adverse events typical of stimulant drugs (including but not limited to euphoria, hypervigilance, and increased energy). Data from these studies did not reveal any abuse-related adverse events at doses of SDX up to 60 mg.

In the oral HAP study, the adverse event of increased energy was reported more with the active comparators (phentermine and Focalin X) than SDX. Participants taking SDX reported increased energy at frequencies similar to placebo. Euphoric mood was also reported in greater frequencies with the active comparators than either dose of SDX. However, as HHS notes, both doses of SDX had a higher frequency of euphoric mood than placebo (HHS Review, 2021). 9

The IV HAP study reported adverse events of both euphoric mood and hypervigilance with SDX API; however, the frequencies observed were less than those observed with d-MPH API (HHS Review, 2021).

Similarly, the IN HAP study reported adverse events of both euphoric mood and hypervigilance to a greater extent with d-MPH API than with SDX API. However, subjects treated with SDX API reported euphoric mood and hypervigilance to a greater extent than placebo-treated subjects (HHS Review, 2021).

As summarized by HHS, abuse-related adverse events occur less frequently in SDX- treated subjects than in those treated with d-MPH from the Phase 1 and HAP studies, where SDX was evaluated as a single ingredient. However, SDX treated subjects reported more abuse- related adverse events than those treated with placebo (HHS Review, 2021).

Phase 2/3 studies

According to HHS, there were no Phase 2 or 3 studies conducted using SDX alone.

Factor 3. The State of Current Scientific Knowledge Regarding SDX

Chemistry

As stated in the HHS review, SDX is a new molecular entity identified by the drug development code KP415. Chemically, SDX consists of a single molecule of d-MPH, covalently attached via a carbamate bond to a methylene oxide linker. The methylene oxide linker is covalently attached to the nitrogen of a pyridine ring of a nicotinoyl-L-serine group that forms a pyridinium quaternary salt. The carbamate bond confers chemical stability to the molecule in acidic and basic media, limiting the rate of release of d-MPH from SDX (Ghosh and Brindisi, 2015). SDX as a quaternary salt can exist as an ion pair where the pyridinium portion carries the positive charge that requires a counter ion (e.g., chloride). However, SDX as a quaternary ammonium structure may result in compounds with low lipophilicity that have low blood-brain barrier penetration and low gastrointestinal absorption (Holzer, 2009).

SDX is chemically known as 3-[[[(1S)-1-carboxy-2-hydroxyethyl]-amino]carbonyl]-1- [[[[(2R)-2-[(1R)-2-methoxy-2-oxo-1-phenylethyl]-1- piperidinyl]carbonyl]oxy]methyl]pyridinium chloride. SDX is identified by the CAS register number 1996626-30-2. The molecular formula of SDX is C25H30ClN3O8 and a molecular weight of 535.98 g/mol. The inner salt of SDX has a molecular formula of C25H29N3O8 and a molecular weight of 500.5 g/mol. The melting point of SDX is 202 °C to 208 °C (HHS Review, 2021).

SDX is a white to off-white crystalline solid that is freely soluble in water at pH 1.2 (333.5 mg/mL), 2.9 (382.22 mg/mL), and 5.8 to 6.8 (> 500 mg/mL). The solubility of SDX at pH higher than 6.8 was not determined because saturated solutions of SDX degraded under basic conditions after 24 hours (HHS Review, 2021). According to HHS, the Sponsor estimated that SDX has limited solubility (< 1 mg/mL) in non-polar organic solvents such as n-heptane, toluene, and dichloromethane. In polar solvents, such as acetone or acetonitrile, solubility of

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SDX is slightly increased (~ 1 mg/L). Additionally, solubility of SDX also increased in polar protic solvents such as ethanol (~9 mg/mL) and methanol (> 50 mg/mL). In dimethyl sulfoxide and dimethylformamide, SDX solubility was very high (> 150 mg/mL). The Sponsor also reported an octanol/water partition coefficient (Log P/D) of -0.84 at pH 1.2. At this value, SDX as a quaternary salt and a pH at which the serine moiety -COOH is unionized, will have limited absorption due to its hydrophilicity (HHS Review, 2021).

HHS notes that SDX has three chiral centers, and, thus, eight optical isomers of the molecule can exist. However, it is an enantiopure compound of defined configuration at these three chiral centers and identified by the (S) and (R) prefix (HHS Review, 2021).

According to HHS, the synthesis of SDX occurs in four steps and requires d-MPH (a schedule II drug) as the starting material. SDX is synthesized with all chiral and non-chiral starting materials being readily available. In the final steps, the crude SDX is purified by recrystallizations.

SDX will be marketed in combination with d-MPH as immediate-release capsules that contain fixed molar dose ratios of 70% SDX to 30 % d-MPH. Each molecule of d- MPH weighs 269.77 grams, and considering this, the proposed marketed SDX doses of 28 mg, 42 mg, and 56 mg of SDX would be equivalent to 14 mg, 21 mg, and 28 mg of d-MPH, respectively (HHS Review, 2021). Thus, the FDA-approved combination drug products (SDX/d-MPH) would be available in three strengths of 26.1 mg/5.2 mg, 39.2 mg/7.8 mg, and 52.3 mg/10.4 mg of serdexmethylphenidate/dexmethylphenidate, respectively.

As HHS States, the d-MPH immediate-release component in the drug product is intended to provide a fast onset of action, while the SDX component is intended to provide a delayed release of d-MPH, based on its delayed metabolism and absorption (see the Pharmacokinetics section below).

In Vitro Stability Studies

The HHS Review states that the Sponsor performed in vitro studies to determine if SDX (a prodrug of d-MPH) could convert to d-MPH under hydrolytic conditions. Hydrolytic experiments were conducted across a pH range of 1 and 13, at SDX concentrations of 5 mg/mL or 50 mg/mL (using 50 mg or 500 mg of SDX in 10 mL of buffer solution to obtain solutions of SDX). At room temperature, both concentrations of SDX were stable at pH 1 to 8 for up to 24 hours, with no d-MPH or carboxylic acid derivatives such as ritalinic acid (resulting from cleavage of the methyl ester group on d-MPH) and SDX-acid (resulting from cleavage of the methyl ester group on SDX). Ritalinic acid and SDX-acid are both pharmacologically inactive degradation products, with ritalinic acid formed from SDX or d-MPH, and SDX-acid formed from SDX. As HHS notes, SDX at pH 9, was stable for at least 1 hour, with minimal conversion to d-MPH at a minimum of 6 hours. SDX at pH 11, at a concentration of 5 mg/mL aqueous solution, was rapidly converted to ritalinic acid with no d-MPH detected. However, hydrolysis of 50 mg/mL solution of SDX to ritalinic acid occurred at a lower rate (HHS Review, 2021).

Pharmacokinetics

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In this section as described by HHS, data on the absorption, distribution, metabolism, and excretion of SDX is discussed. Additionally, data is presented below on the pharmacokinetic parameters measured with a single dose of SDX administered by the oral, IN, and IV routes in healthy individuals.

Absorption

According to HHS, the Sponsor conducted several studies to evaluate the sites of absorption and metabolism of SDX, since the activity of SDX relies on its conversion to d-MPH. The charged nature of the SDX quaternary salt (see Chemistry Section above) renders SDX to have poor permeability across cellular membranes, resulting in poor systemic absorption and poor tissue penetration. As noted by HHS, and stated by the Sponsor, a very small fraction of the drug is absorbed in the intestinal tract after oral administration, where the drug remains intact until it is metabolized to d-MPH in the lower intestine. Pharmacokinetic results from the IV HAP study and several oral studies suggests that the absolute oral bioavailability of SDX is lower than 3 percent (the range is 1 percent to 4 percent), and that the small fraction of the drug that is absorbed remains mostly intact in blood until excreted unchanged in the urine (HHS Review, 2021).

As stated by HHS, with oral administration of the combination product containing SDX and d-MPH, early exposure to d-MPH is dependent on the immediate release of the d-MPH component of the product, whereas the delayed exposure to d-MPH is dependent on the conversion of SDX to d-MPH in the lower intestines. However, HHS notes that the enzymes involved in the conversion process of SDX to d-MPH have not been identified.

Distribution

As HHS notes, in vitro studies demonstrated that SDX and d-MPH exhibited minimal binding to human plasma proteins (56% for SDX vs. 47.3% for d-MPH). As HHS notes, the Sponsor stated that SDX has a low mean body weight-normalized volume of distribution, which suggests that SDX is not distributed to the tissues and remains in the blood compartment, in contrast to d-MPH.

Metabolism

According to HHS, the most abundant metabolite identified in urine, feces, and plasma upon a single oral dose of [14C]-SDX administered to healthy volunteers was ritalinic acid. There was only one unique metabolite of SDX identified in the feces at very low levels, and thus not absorbed. There were no unique SDX metabolites detected in plasma (HHS Review, 2021).

HHS notes that the Sponsor concluded that SDX is stable in fresh human whole blood, plasma, simulated intestinal fluid, and simulated gastric fluid and in human liver, human kidney, human intestinal, and human lung S9 fractions based on results from an in vitro metabolic stability study of SDX. A slow disappearance of SDX was observed at 90 minutes (73.8 percent remained) in whole blood, with minimal formation of d-MPH and no formation of ritalinic acid (HHS Review, 2021).

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Excretion

According to HHS, data from the oral administration of a single [14C]-SDX dose in human volunteers was used to determine excretion of SDX in humans. At 168 hours after oral SDX administration, 62.1 percent and 36.8 percent of radioactivity was recovered in urine and feces, respectively (98.9 percent total recovery). At 72 hours post dose, the mean cumulative percentages of radioactive dose recovered urine corresponded to SDX (0.43 percent), SDX- derived d-MPH (2.74 percent), ritalinic acid (45.2%), and other minor metabolites (HHS Review, 2021).

Following oral administration of SDX, ritalinic acid was the most abundant metabolite in plasma, urine, and feces. According to HHS and the Sponsor, 18 percent of the SDX dose is excreted as ritalinic acid in feces. The Sponsor postulates that this percentage of SDX may represent the amount of SDX-derived ritalinic acid formed in the lower intestine, which may be less permeable to ritalinic acid than to the SDX-derived d-MPH, or that excretion takes place faster than absorption (HHS Review, 2021).

Pharmacokinetic Data

According to HHS, 10 studies were conducted by the Sponsor to address the pharmacokinetic profile of SDX administered alone or in combination with d-MPH under several conditions (fed and fasted), in different populations (healthy volunteers, patients, adult and young patients), and after single- and multiple-dose administration. As Factor 2 describes, studies were conducted as part of the HAP assessment where healthy volunteers with a prior history of recreational use of stimulants were administered single doses of SDX and of d-MPH by the oral, IN, and IV routes.

Results from the oral HAP study show that single doses of 120 mg and 240 mg SDX have geometric mean maximum plasma concentrations (Cmax) of 46.9 ng/mL and 108.4 ng/mL, respectively. The median time to maximal plasma concentration (Tmax) was two hours (with a minimal value of 0.5 hours and a maximum value of 8.1 hours) for the 120 mg SDX dose and a Tmax of three hours (with a minimal value of 0.5 hours and a maximum value of 8.2 hours) for the 240 mg SDX dose. The median half-life for the 120 mg SDX dose was 6.42 hours (with a minimal value of 3.33 hours and a maximum value of 9.62 hours) and 6.27 hours for the 240 mg SDX dose (with a minimum value of 3.3 hours and a maximum value of 9.37 hours).

As stated by HHS, oral administration of single doses of 120 mg and 240 mg SDX, increased the concentration of d-MPH slowly with a geometric mean Cmax of 6.8 ng/mL and 12.5 ng/mL respectively, with a median Tmax of 9 hours (with a minimal value of 6 hours and a maximum value of 36 hours) and 11 hours (with a minimal value of 7 hours and a maximum value of 36 hours), respectively. SDX-derived d-MPH had a median half-life of 10 hours for the 120 mg dose (with a minimal value of 5.04 hours and a maximum value of 18.93 hours) and 10.8 hours for the 240 mg dose (with a minimum value of 3.94 hours and a maximum value of 18.29 hours).

As HHS notes, IN administration of a single dose of 80 mg SDX had a geometric mean Cmax of 2,739 ng/mL, a median Tmax of 17.5 minutes (with a minimal value of 16 minutes and

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a maximum value of 48 minutes), and a median half-life of 3.30 hours (with a minimal value of 2.19 hours and a maximum value of 8.4 8 hours). Pharmacokinetic data suggest that there was a very low-level conversion of SDX to d-MPH at the IN mucosa since geometric mean Cmax values reached 6.43 ng/mL at approximately 30 minutes (Tmax) for SDX-derived d-MPH. The Cmax of SDX-derived d-MPH was 33-fold lower than the maximal levels following IN administration of 40 mg d-MPH (HHS Review, 2021).

Following 1-minute IV administration of 30 mg SDX and of 15 mg d-MPH, plasma concentrations of both drugs rose rapidly. The mean Cmax values for SDX were 3,005 ng/mL within 5 minutes, with very limited conversion to d-MPH. The mean Cmax values for d-MPH were 60.1 ng/mL (standard deviation ± 15.2, N = 30) at 15 minutes post dose. After reaching the Cmax, plasma concentrations for both drugs declined in a monophasic manner (HHS Review, 2021).

As summarized by HHS, these studies confirmed that the concentration of d-MPH derived from SDX increases slowly to reach Cmax at approximately 10 hours after oral administration, with a half-life of approximately 10 hours. Within the first hour after IN administration, there is limited conversion of SDX to d-MPH. Moreover, with IV administration, SDX is not metabolized to d-MPH in blood.

Medical Use in the United States

On March 2, 2021, FDA approved the NDA 212994 for AZSTARYS, a combination drug product containing d-MPH and SDX. Thus SDX has a currently accepted medical use in the United States.

Factor 4. History and Current Pattern of Abuse of SDX As mentioned by HHS, there is no information on the history and current pattern of abuse for SDX, since it has not been marketed, legally or illegally, in the United States or any country. Data from preclinical and clinical studies indicate that the abuse potential of SDX is similar to that of schedule IV stimulants. Therefore, SDX is likely to be abused in a manner similar to schedule IV stimulants such as phentermine (HHS review, 2021).

DEA conducted a search of the NFLIS, database for SDX encounters. No records of encounters by law enforcement were identified, which is consistent with the fact that SDX is a new molecular entity.

Factor 5. The Scope, Duration, and Significance of Abuse of SDX

As mentioned by HHS, information on Factor 5 is limited because SDX is not marketed in the United States or any country. HHS notes that SDX is pharmacological similar to schedule IV stimulants (as shown in the preclinical and clinical study data; see Factors 1 and 2 above).

DEA conducted a comprehensive search and found no evidence of law enforcement encounters of SDX in the United States. Thus, it is likely that SDX has an abuse potential similar to that of phentermine, a schedule IV drug (HHS review, 2021).

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Factor 6. What, If Any, Risk to the Public Health

As stated by HHS, abuse potential of a drug is considered an indication of its risk to public health (HHS review, 2021). Data from the pre-clinical and clinical studies (described in Factors 1 and 2) demonstrate there are signals that indicate that SDX has an abuse potential similar to that of the schedule IV stimulant phentermine. Therefore, SDX is likely to pose a public health risk to a degree similar to schedule IV stimulants.

Factor 7. SDX's Psychic or Physiological Dependence Liability

As described by HHS (HHS review, 2021), SDX produced positive subjective responses to ratings of Drug Liking and Drug High in a human abuse potential study. The responses were significantly higher than placebo and similar to phentermine, a schedule IV stimulant. HHS concludes that SDX can produce psychic dependence to a similar extent as phentermine. According to HHS, there are no animal or human studies investigating physical dependence potential of SDX. HHS further states that withdrawal symptoms occur after an abrupt cessation following a prolonged high dosage administration of CNS stimulants. However, following an abrupt cessation of the SDX/d-MPH combination treatment in clinical studies involving a prolonged dosage administration of this combination, adverse effects associated with withdrawal did not occur.

Factor 8. Whether SDX Is an Immediate Precursor of a Substance Already Controlled

HHS states that SDX is not known or expected to be an immediate precursor in the chemical synthesis of any substance controlled under the CSA. SDX is not an immediate precursor of any substance already controlled in the CSA as defined in 21 U.S.C 802(23).

III. Findings for Schedule Placement Pursuant to 21 U.S.C. 812(b)

21 U.S.C. 812(b) requires the evaluation of a substance’s abuse potential, accepted medical use, safety for use under medical supervision, and physical or psychological dependence for scheduling under the CSA as a controlled substance. After consideration of the above eight factors determinative of control of a substance (21 U.S.C. 811(c)), and a review of the scientific and medical evaluation and scheduling recommendation provided by HHS, DEA finds that SDX meets the following criteria for placement in schedule IV of the CSA pursuant to 21 U.S.C. 812 (b)(4).

1) SDX has a low potential for abuse relative to the drugs or other substances in Schedule III. Orally administered SDX, is metabolized in the large (lower) intestines to d-MPH (a schedule II drug). However, the abuse potential is lower than that of schedule II drugs and is comparable to that of schedule IV phentermine. An oral HAP study is the basis for this conclusion, where SDX at oral doses of 120 mg and 240 mg showed a lower or similar abuse potential as phentermine, a schedule IV drug, on all endpoints. When compared to placebo, SDX demonstrated greater abuse potential at either dose of SDX.

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Because SDX is similar to phentermine in its abuse potential, SDX has a low potential for abuse relative to the drugs or other substances in schedule III.

2) SDX has a currently accepted medical use in the United States. FDA recently approved a NDA of new product with SDX listed as one of the active ingredients for use in treatment of ADHD. Thus, SDX has a currently accepted medical use in treatment in the United States.

3) Abuse of SDX may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III.

As HHS notes, the physical dependence of SDX was not studied in animal models or dedicated human studies. Symptoms of a withdrawal syndrome resulting from drug discontinuation are a hallmark of physical dependence. However, according to HHS, there was no adverse events indicative of withdrawal from discontinuation of the SDX/d-MPH combination treatment in clinical studies.

The pharmacological profile (see Factor 2) and the chemistry profile (see Factor 3) suggests that the physical dependence liability of SDX is likely low and determined by the cumulative plasma levels of d-MPH reached upon chronic oral administration of multiple high doses of SDX.

In a human abuse potential study, SDX, at therapeutic and supra-therapeutic doses, produced positive subjective responses such as Drug Liking and Drug High similar to those of phentermine and higher than placebo. These data suggest that SDX can produce psychological dependence to a similar extent as phentermine, a schedule IV substance. Thus, abuse of SDX may lead to limited physical or psychological dependence relative to substances in schedule III.

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References

Department of Health and Human Services (HHS) Review (2021). Basis for the Recommendation to Control Serdexmethylphenidate and Its Salts in schedule IV of the Controlled Substances Act (CSA).

Ghosh, A. K. and Brindisi M. (2015). Organic carbamates in drug design and medicinal chemistry. J Med Chem 58(7): 2895-2940.

Holzer, P. (2009). Opioid receptors in the gastrointestinal tract. Regul Pept 155(1-3): 11-17.

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