METHODS OF SLOWING BRAIN VOLUME LOSS

The disclosure relates to methods of slowing brain volume loss. In certain aspects, methods of slowing brain volume loss in a patient with multiple sclerosis are disclosed.

TECHNICAL FIELD

The present disclosure relates to methods of slowing brain volume loss, and, in particular, methods of slowing brain volume loss in a patient having multiple sclerosis (MS).

BACKGROUND

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system affecting 2.5 million people worldwide. The disease is characterized by demyelination and axonal loss leading to neurological impairment and severe disability. The two main subtypes of MS are relapsing forms of MS (RMS) which represent 85% of MS patients and include relapsing-remitting disease (RRMS), clinically isolated syndrome, and active secondary progressive disease; and primary progressive MS (PPMS) which affects only 15% of MS patients.

Brain atrophy, measured as brain volume loss on MM, occurs naturally with aging and the annualized percent brain volume change (PBVC/y) is about −0.2% to about −0.3% for healthy individuals that do not have MS (De Stefano N, et al. J Neural Neurosurg Psychiatry 2016; 87:93-99. doi:10.1136/jnnp-2014-309903). MS patients, however, have a PBVC/y of at least about −0.5% and may lose brain volume around three to five times faster than healthy individuals that do not have MS, starting in the earliest, clinically silent stages of the disease. In MS, just as in other debilitating neurological conditions such as Alzheimer's or Parkinson's, atrophy has been associated with both cognitive impairment and disability, and the more atrophy an MS patient has, the worse their disability is, and is likely to be. Once lost, brain tissue cannot be recovered.

While there are now therapies available that show promising effects on brain volume loss, there persists an unmet need for new products with high efficacy in preventing brain volume loss while being safe and well tolerated.

SUMMARY

In embodiments, the present disclosure is directed to a method for slowing brain volume loss in a patient in need thereof, comprising administering to the patient ponesimod using a regimen that is effective to slow brain volume loss.

In embodiments, the present disclosure is directed to a method for slowing brain volume loss in a patient in need thereof, comprising assessing cognitive deficiencies or physical deficiencies in the patient; and administering ponesimod to the patient using a regimen that is effective to slow brain volume loss.

In embodiments, the present disclosure is directed to a method of slowing brain volume loss in a patient in need thereof, comprising administering ponesimod to the patient using a regimen that is effective to slow brain volume loss relative to a patient having substantially similar baseline disease characteristics and receiving a standard of care treatment that does not comprise ponesimod.

In embodiments, the present disclosure is directed to ponesimod for use in a method of slowing brain volume loss in a patient in need thereof, wherein ponesimod is administered to the patient using a regimen that is effective to slow brain volume loss.

In embodiments, the present disclosure is directed to ponesimod for use in a method of slowing brain volume loss in a patient in need thereof, wherein said method comprises assessing cognitive deficiencies or physical deficiencies in the patient; and administering ponesimod to the patient using a regimen that is effective to slow brain volume loss.

In embodiments, the present disclosure is directed to ponesimod for use in a method of slowing brain volume loss in a patient in need thereof, wherein ponesimod is administered to the patient using a regimen that is effective to slow brain volume loss relative to a patient population having substantially similar baseline disease characteristics and receiving a standard of care treatment that does not comprise ponesimod.

In embodiments, the present disclosure is directed to the use of ponesimod in the preparation of a medicament for slowing brain volume loss in a patient in need thereof, wherein said medicament is adapted to be administered using a regimen that is effective to slow brain volume loss.

In embodiments, the present disclosure is directed to the use of ponesimod in the preparation of a medicament for slowing brain volume loss in a patient in need thereof, wherein said medicament is adapted to be administered using a regimen that is effective to slow brain volume loss relative to a patient population having substantially similar baseline disease characteristics and receiving a standard of care treatment that does not comprise ponesimod.

In certain aspects, the methods of the disclosure are performed on a human patient suffering from multiple sclerosis. In some embodiments, the patient's multiple sclerosis is relapsing multiple sclerosis. In other embodiments, the relapsing multiple sclerosis comprises relapsing-remitting disease, clinically isolated syndrome, or active secondary progressive disease.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In the present disclosure the singular forms “a”, “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to “a material” is a reference to at least one of such materials and equivalents thereof known to those skilled in the art, and so forth.

When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiments and such a combination is considered to be another embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself.

In some aspects, the present disclosure is directed to a method for slowing brain volume loss in a patient in need thereof, comprising administering to the patient ponesimod using a regimen that is effective to slow brain volume loss.

In some aspects, the present disclosure is directed to a method of slowing brain volume loss in a patient in need thereof, comprising assessing cognitive deficiencies or physical deficiencies in the patient; and administering ponesimod to the patient using a regimen that is effective to slow brain volume loss.

In some aspects, the present disclosure is directed to a method of slowing brain volume loss in a patient in need thereof, comprising administering ponesimod to the patient using a regimen that is effective to slow brain volume loss relative to a patient having substantially similar baseline characteristics and receiving a standard of care treatment that does not comprise ponesimod.

In some aspects, the present disclosure is directed to ponesimod for use in a method of slowing brain volume loss in a patient in need thereof, wherein ponesimod is administered to the patient using a regimen that is effective to slow brain volume loss.

In some aspects, the present disclosure is directed to ponesimod for use in a method of slowing brain volume loss in a patient in need thereof, wherein said method comprises assessing cognitive deficiencies or physical deficiencies in the patient; and administering ponesimod to the patient using a regimen that is effective to slow brain volume loss.

In some aspects, the present disclosure is directed to ponesimod for use in a method of slowing brain volume loss in a patient in need thereof, wherein ponesimod is administered to the patient using a regimen that is effective to slow brain volume loss relative to a patient population having substantially similar baseline disease characteristics and receiving a standard of care treatment that does not comprise ponesimod.

In some aspects, the present disclosure is directed to the use of ponesimod in the preparation of a medicament for slowing brain volume loss in a patient in need thereof, wherein said medicament is adapted to be administered using a regimen that is effective to slow brain volume loss.

In some aspects, the present disclosure is directed to the use of ponesimod in the preparation of a medicament for slowing brain volume loss in a patient in need thereof, wherein said medicament is adapted to be administered using a regimen that is effective to slow brain volume loss relative to a patient population having substantially similar baseline disease characteristics and receiving a standard of care treatment that does not comprise ponesimod.

In some aspects, the methods of the disclosure are performed on a human patient suffering from multiple sclerosis. In some embodiments, the patient's multiple sclerosis is relapsing multiple sclerosis. In other embodiments, the relapsing multiple sclerosis comprises relapsing-remitting disease, clinically isolated syndrome, or active secondary progressive disease.

In some aspects, the present disclosure is directed to ponesimod in combination with an additional therapeutic agent. For example, the therapeutic agent may be an agent that enhances or normalizes the reduction of brain volume loss in the patient. In some aspects, the additional therapeutic agent is teriflunomide, leflunomide, methyl fumarate, dimethyl fumarate, (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate, or 2-(2,5-dioxopyrrolidin-1-yl)ethyl methyl (2E)but-2-ene-1,4-dioate.

In some aspects, the cognitive deficiencies are information processing; memory; attention/concentration; executive functions; visuospatial functions; or verbal fluency. In certain aspects, the information processing deficiencies comprise deficiencies associated with information gathered by the five senses. In certain aspects, the memory deficiencies comprise deficiencies associated with acquiring, retaining and retrieving new information. In certain aspects, the executive functions deficiencies comprise deficiencies associated with planning and prioritizing. In certain aspects, the visuospatial functions deficiencies comprise deficiencies associated with visual perception and constructional abilities. In certain aspects, the verbal fluency deficiencies comprise deficiencies associated with word-finding.

In some aspects, the physical deficiencies are vision, hearing, speaking, swallowing, breathing, muscle weakness, hand-eye coordination, balance and gait. In certain aspects, the vision deficiencies comprise double vision, blurriness, pain, and problems seeing contrast. In certain aspects, the hearing deficiencies comprise hearing loss and deafness. In certain aspects, the speaking deficiencies comprise slurring, poor articulation and volume control issues. In certain aspects, the muscle weakness comprises pain, tingling, and numbness of the arms and legs.

Given the slowing of brain volume loss resulting from the methods disclosed herein, a treating physician has additional treatment options. For example, if an assessment indicates a high degree of cognitive or physical deficiencies, a patient can be administered ponesimod as opposed to other standard of care options. In addition, if a patient currently receiving a standard of care treatment is experiencing a high degree of cognitive or physical deficiencies, the treating physician may transition the patient to a ponesimod treatment regimen.

In some aspects, the regimen is effective to slow brain volume loss by at least about 20% relative to a patient having substantially similar baseline disease characteristics and receiving a standard of care treatment that does not comprise ponesimod. Such a relative analysis is disclosed in Example 1. In some aspects, the relative slowing of brain volume loss is at least 25%, 30%, or 35%.

In some aspects, the regimen is effective to slow brain volume loss by about 20% to about 35% relative to a patient having substantially similar baseline disease characteristics and receiving a standard of care treatment that does not comprise ponesimod. In some aspects, the relative slowing of brain volume loss is about 20% to about 25%, about 25% to about 30%, or about 30% to about 35%.

Typically, the relative slowing of brain volume loss demonstrated by the methods disclosed herein results after at least about a two year time period from initiation of treatment with ponesimod and the standard of care treatment. In other embodiments, the relative slowing of brain volume loss demonstrated by the methods disclosed herein results after about a three, four, or five year time period. In certain embodiments, the ponesimod regimen is effective to slow brain volume loss by about 25% to about 30% relative to a patient having substantially similar baseline disease characteristics and receiving a standard of care treatment comprising teriflunomide administered at about 14 mg orally once daily over at least about a two year time period.

In certain aspects, the patient has a neurodegenerative disease other than multiple sclerosis. In certain aspect the patient has Alzheimer's disease. In certain aspects, the patient has Parkinson's disease.

In certain aspects, the brain volume loss comprises loss of white matter or loss of grey matter in the brain.

As used herein, the term “ponesimod” refers to the compound (R)-5-[3-chloro-4-(2,3-dihydroxy-propoxy)-benz[Z]ylidene]-2-([Z]-propylimino)-3-o-tolyl-thiazolidin-4-one, which has the following structure:

In some embodiments, “ponesimod” also refers to pharmaceutically acceptable salts of ponesimod. The term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example Handbook of Pharmaceutical Salts. Properties, Selection and Use, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and Pharmaceutical Salts and Co-crystals, Johan Wouters and Luc Quéré (Eds.), RSC Publishing, 2012.

It is to be understood that the present disclosure encompasses ponesimod in any form including amorphous as well as crystalline forms. It is further to be understood that crystalline forms of ponesimod encompasses all types of crystalline forms including polymorphs, solvates and hydrates, salts and co-crystals (when the same molecule can be co-crystallized with different co-crystal formers) provided they are suitable for pharmaceutical administration. In some embodiments, ponesimod is in crystalline form A or crystalline form C as described in WO 2010/046835, incorporated herein by reference. In some embodiments, ponesimod is in crystalline form C.

It should be noted that the amounts of ponesimod described herein are set forth on a ponesimod free base basis. That is, the amounts indicate that amount of the ponesimod molecule administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).

In some embodiments, the effective regimen comprises a daily dose of ponesimod. In some embodiments, the daily dose of ponesimod is administered orally.

In some embodiments, the daily dose of ponesimod is administered once daily.

In some embodiments, the daily dose of ponesimod is about 15 to about 25 mg. In further embodiments, the daily dose of ponesimod is about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg. In certain embodiments, the daily dose of ponesimod is about 20 mg.

In some embodiments, about 20 mg of ponesimod is administered orally once daily.

In other embodiments, the effective regimen comprises an up-titration, followed by a daily maintenance dose of ponesimod. An up-titration is a dosing procedure in which the daily dose of ponesimod is gradually increased over a period of days, culminating with administration of the maintenance dose.

In some embodiments, the regimen comprises an up-titration at the initiation of the method of the disclosure. In other embodiments, the regimen comprises an up-titration upon re-initiation of the method after a discontinuation of the method of the disclosure. As used herein, “upon re-initiation of the method after a discontinuation” means an interruption of the administration of ponesimod of at least one, at least two or preferably at least 3 days before treatment is re-initiated. In some embodiments, the regimen comprises an up-titration step at initiation of the method or upon re-initiation of the method after a discontinuation.

In some embodiments of the methods of the disclosure, the up-titration regimen one disclosed in U.S. Pat. No. 10,220,023, incorporated herein by reference. For example, in certain aspects, the up-titration comprises administering orally once daily about 2 mg of ponesimod on days 1 and 2; about 3 mg of ponesimod on days 3 and 4; about 4 mg of ponesimod on days 5 and 6; about 5 mg of ponesimod on day 7; about 6 mg of ponesimod on day 8; about 7 mg of ponesimod on day 9; about 8 mg of ponesimod on day 10; about 9 mg of ponesimod on day 11; and about 10 mg of ponesimod on days 12, 13, and 14.

In other embodiments of the methods of the disclosure, the up-titration comprises administering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; 9 mg of ponesimod on day 11; and 10 mg of ponesimod on days 12, 13, and 14.

In some embodiments, the maintenance dose is about 20 mg of ponesimod once daily.

In some embodiments, the regimen comprises an up-titration step at initiation of the method or upon re-initiation of the method after a discontinuation, comprising administering orally once daily 2 mg of ponesimod on days 1 and 2; 3 mg of ponesimod on days 3 and 4; 4 mg of ponesimod on days 5 and 6; 5 mg of ponesimod on day 7; 6 mg of ponesimod on day 8; 7 mg of ponesimod on day 9; 8 mg of ponesimod on day 10; and 9 mg of ponesimod on day 11; 10 mg of ponesimod on days 12, 13, and 14, followed by the administering of the 20 mg of ponesimod once daily thereafter.

As used herein, the term “teriflunomide” refers to the compound Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide, which has the following structure:

In some embodiments, “teriflunomide” also refers to pharmaceutically acceptable salts of teriflunomide. The term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example Handbook of Pharmaceutical Salts. Properties, Selection and Use, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008 and Pharmaceutical Salts and Co-crystals, Johan Wouters and Luc Quéré (Eds.), RSC Publishing, 2012.

It is to be understood that the present disclosure encompasses teriflunomide in any form including amorphous as well as crystalline forms. It is further to be understood that crystalline forms of teriflunomide encompasses all types of crystalline forms including polymorphs, solvates and hydrates, salts and co-crystals (when the same molecule can be co-crystallized with different co-crystal formers) provided they are suitable for pharmaceutical administration.

It should be noted that the amounts of teriflunomide described herein are set forth on a teriflunomide free base basis. That is, the amounts indicate that amount of the teriflunomide molecule administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).

Leflunomide (e.g., 5-methyl-N-(4-(trifluoromethyl)phenyl)isoxazole-4-carboxamide) can be used for the treatment of multiple sclerosis. In vivo leflunomide is metabolized to the active metabolite teriflunomide which is responsible for leflunomide's activity in vivo. Leflunomide can be prepared according to procedures known in the art, for example as described in U.S. Pat. No. 4,284,786.

Dimethyl fumarate (e.g., DMF) has been described in WO 00/030622 to be useful for the treatment of autoimmune diseases and Tecfidera® has been approved for the treatment of relapsing forms of multiple sclerosis. Dimethyl fumarate can be prepared according to procedures known in the art for example as described in EP 0312697 A2.

Methyl fumarate (e.g., monomethyl fumarate or MMF) has been shown to be a pharmacologically active metabolite of dimethyl fumarate. Methyl fumarate can be prepared according to procedures known in the art for example as described in EP 0312697 A2.

(N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (e.g.) XP23829) is a prodrug that is rapidly converted to monomethyl fumarate. XP23829 is currently in clinical development for the treatment of relapsing forms of multiple sclerosis. (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate and the preparation thereof is described in WO 2010/022177.

2-(2,5-Dioxopyrrolidin-1-yl)ethyl methyl (2E)but-2-ene-1,4-dioate (e.g., ALKS 8700) is a prodrug that rapidly converts to monomethyl fumarate. ALKS 8700 is currently in clinical development for the treatment of multiple sclerosis. 2-(2,5-Dioxopyrrolidin-1-yl)ethyl methyl (2E)but-2-ene-1,4-dioate and the preparation thereof is described in WO 2014/152494.

As used herein, the term “standard of care treatment” refers to a physician-prescribed treatment, and, in particular a prescribed treatment for MS. In some embodiments, the standard of care comprises, consists of, or consists essentially of administering an MS treatment that has been approved by a regulatory authority. In some embodiments, the standard of care treatment is Interferon (IFN) β-1a 30 mcg i.m. once weekly (Avonex®), IFN β-1a 22 or 44 mcg s.c. 3 times weekly (Rebif®), IFN β-1b 250 mcg s.c. every other day (Betaferon®, Extavia®), Pegylated IFN β-1a 125 mcg subcutaneously every 2 weeks (Plegridy®), Glatiramer acetate 20 mg s.c. once a day (o.d.) or 40 mg subcutaneously 3 times weekly (Copaxone®), Glatiramer acetate 20 mg s.c. o.d. (Glatopa®), Natalizumab 300 mg i.v. every 4 weeks (Tysabri®), Mitoxantrone i.v. every 3 months (Novantrone®), Alemtuzumab concentrate for solution for infusion, 12 mg alemtuzumab in 1.2 mL (10 mg/mL) (Lemtrada®), Fingolimod 0.5 mg orally o.d. (Gilenya®), Teriflunomide 7 mg, 14 mg o.d. (Aubagio®), Dimethyl fumarate (BG-12) gastro-resistant hard capsules 120/240 mg twice daily (Tecfidera®), or Cladribine 40 to 100 mg orally per treatment week (Mavenclad®).

In some embodiments, the standard of care treatment comprises a S1P receptor modulator that is not ponesimod.

In other embodiments, the standard of care treatment comprises teriflunomide. In some embodiments, the standard of care treatment comprises administration of about 14 mg of teriflunomide orally once daily.

With respect to baseline disease characteristics, baseline refers to a time period prior to initiation of treatment with ponesimod and/or standard of care treatment. This time period is typically up to about 45 days prior to initiation of treatment with ponesimod and/or standard of care treatment, including, for example, up to about 40 days, up to about 35 days, up to about 30 days, up to about 25 days, up to about 20 days, up to about 15 days, or up to about 10 days prior to initiation of treatment with ponesimod. Examples of baseline disease characteristics are disclosed in Example 1.

The following Example is provided to illustrate some of the concepts described within this disclosure. While the Example is considered to provide an embodiment, it should not be considered to limit the more general embodiments described herein.

Study Design

A prospective, multicenter, randomized, double-blind, active controlled, parallel-group, superiority study to compare the efficacy and safety of ponesimod to teriflunomide in subjects with brain volume loss was conducted. The study was designed to compare the efficacy, safety, and tolerability of ponesimod 20 mg vs teriflunomide 14 mg in adult subjects with brain volume loss.

Randomization: Subjects were randomized in a 1:1 ratio to ponesimod 20 mg or teriflunomide 14 mg, stratified by prior use of MS disease modifying treatment (DMT) in the last two years prior to randomization (yes, no) and by baseline expanded disability status scale (EDSS) score (EDSS≤3.5, EDSS>3.5).

Inclusion Criteria

This study enrolled adult male and female subjects aged 18 to 55 years with established diagnosis of MS, as defined by the 2010 revision of McDonald Diagnostic Criteria [Polman C H, et al.Diagnostic criteria for multiple sclerosis:2010revisions to the McDonald criteria. Ann Neurol. 2011; 69(2):292-302], with relapsing course from onset (i.e., relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis [SPMS] with superimposed relapses). The trial included up to a maximum 15% of subjects with SPMS with superimposed relapses.

Subjects had active disease evidenced by one or more MS attacks with onset within the period of 12 to 1 months prior to baseline EDSS assessment, or by two or more MS attacks with onset within the 24 to 1 months prior to baseline EDSS assessment, or with one or more gadolinium-enhancing (Gd+) lesion(s) of the brain on an MRI performed within 6 months prior to baseline EDSS assessment. Enrolled subjects were ambulatory with an EDSS score of up to 5.5 inclusive. The subjects were treatment-naïve (i.e., no MS disease-modifying therapy received at any time in the past) or previously treated with interferon (IFN) β-1a, IFN β-1b, glatiramer acetate, dimethyl fumarate, or natalizumab.

Subjects with significant medical conditions or therapies for such conditions (e.g., cardiovascular, pulmonary, immunological, hepatic, ophthalmological, ocular) or lactating or pregnant women were not eligible to enter the study.

Subjects with contraindications to MM or with clinically relevant medical or surgical conditions that, in the opinion of the investigator, would put the subject at risk by participating in the study were not eligible to enter the study.

For an individual subject, the maximum duration of the study was approximately 118 weeks consisting of 6 weeks of screening, 108 weeks of treatment and 4 weeks of safety follow-up. Subjects discontinuing treatment prematurely had an option to stay in a post-treatment observation period (PTOP) for up to 108 weeks.

The study consisted of the following periods:

Treatment period: The double-blind treatment period lasted for 108 weeks. It consisted of a randomization visit, visits at two, four, and 12 weeks after randomization, and 12-weekly visits thereafter.

The EOT visit took place at Week 108 (or earlier in case of premature discontinuation of study drug). In all cases, the EOT visit took place one day after the last dose of study drug but no later than 7 days after the last dose of study drug.

Subjects who completed treatment until Week 108 were eligible to enroll in an extension study conducted under a separate protocol. Subjects who discontinued study drug prematurely for any reason were not eligible for the extension study.

Subjects who prematurely discontinued study drug treatment were subsequently treated according to local standard of care at the investigator's discretion and were followed in the post-treatment observation period.

Teriflunomide is eliminated slowly from plasma. An accelerated elimination procedure was used by all subjects after the last dose of study drug. A safety FU after the last dose of study drug was mandated.

All subjects entered the safety FU period:

For subjects who entered the extension study, the FU period started after the last dose of study drug and ended with a safety FU visit (FU1) 14-22 days after the last dose of study drug or with an abbreviated FU2 23-37 days after the last dose of study drug (if compliance to the teriflunomide accelerated elimination procedure was assessed as not sufficient at FU1).

For subjects who did not enter the extension study, the safety FU period lasted for 30 days after the last dose of study drug and included two safety FU visits (FU1, FU2) at 14-22 and 30-37 days after the last dose of study drug, respectively.

Subjects who prematurely discontinued study treatment enter the PTOP which lasts until 108 weeks after randomization (i.e., planned EOT period). It consisted of an abbreviated schedule of assessments at the time of the originally scheduled 12-weekly visits.

EOS was reached when treatment, safety FU, and, if applicable, PTOP have been completed.

For subjects who completed the 108-week treatment period and entered the extension study, the EOS visit corresponded to the FU visit (FU1) conducted 14-22 days after the last study drug dose or to the abbreviated FU2 visit conducted 23-37 days after the last study drug dose (if needed for compliance reasons with the teriflunomide accelerated elimination procedure).

For all other subjects, the EOS visit corresponded to the 30-day FU visit (FU2) or to the last visit of PTOP (i.e., Week 108 Visit of the PTOP), whichever was last.

The treatment period consisted of an up-titration period (from Day 1 to 14) and a maintenance period (Day 15 until EOT).

During an initial phase of the study, the study drugs in the up-titration period were administered in a double-dummy fashion. Ponesimod (or matching placebo) was presented as tablet, and teriflunomide 14 mg (or matching placebo) was presented as capsule (i.e., daily administration of one tablet and one capsule). At a later phase, the double-dummy material (tablet and capsule) was replaced by the daily administration of one capsule containing either ponesimod or teriflunomide.

In the maintenance period, the study treatment consisted of the daily administration of one capsule containing ponesimod 20 mg or teriflunomide 14 mg.

To reduce the first-dose effect of ponesimod, an up-titration scheme was implemented from Day 1 to Day 14:

Main analysis set for efficacy: The Full Analysis Set (FAS) included all randomized subjects. Subjects were evaluated according to the treatment they were randomized to.

Efficacy variable/timepoint: The endpoint was brain volume loss up to the end of study (EOS). All available data up to EOS, regardless of treatment discontinuation was included (ITT approach).

SeeFIG.1for a schematic representation of the study design.

Statistical Methods

The Full Analysis Set (FAS) included all randomized subjects. In order to adhere to the intention-to-treat principle as much as possible, subjects were evaluated according to the treatment they have been randomized to.

The Per-Protocol Set (PPS) comprises all subjects included in the FAS without any major protocol deviations, that impact the assessment of the endpoint, occurring prior to or at randomization.

The Safety Set (SAF) included all randomized subjects who received at least one dose of study treatment. Subjects were analyzed based on actual treatment taken, not randomized treatment.

Objective

To determine whether ponesimod is more efficacious than teriflunomide in terms of reducing brain volume loss.

Results

Disposition and baseline characteristics: A total of 1133 subjects were randomized to the study, 567 to ponesimod 20 mg and 566 to teriflunomide 14 mg. Overall treatment and study discontinuation were balanced across both treatment arms, 83% of subjects completed treatment. The mean age was 36.7 years and 64.9% of subjects were female. Most subjects were recruited in Europe with 50.6% from EU countries. Mean baseline EDSS score was 2.6 and mean disease duration was 7.6 years. Mean pre-study 12-month relapse rate was 1.3, and 42.6% subjects had ≥1 gadolinium-enhancing (Gd+) T1 lesions. The treatment arms were generally balanced in terms of demographics and baseline disease characteristics.

1. Subject And Treatment Information

A total of 1468 subjects were screened. Of those, 1133 subjects were randomized (567 to ponesimod 20 mg and 566 to teriflunomide 14 mg) across 162 sites in 28 countries, and 1131 subjects received at least one dose of study drug. The disposition of subjects is summarized in Table 1 and a summary of reasons (primary reason) for treatment discontinuation are shown in Table 2. Overall treatment and study discontinuation were balanced across both treatment arms. A total of 6.5% and 2.5% of the subjects discontinued due to AEs or tolerability related reasons in ponesimod 20 mg and teriflunomide 14 mg, respectively, while 1.9% and 4.3% discontinued due to efficacy related reasons. There were 2 deaths reported during the study—both on teriflunomide 14 mg.

1.1 Disposition and Treatment Discontinuation Information

1.2 Demographic and Baseline Characteristics

Randomization was stratified by prior-DMT in the last two years prior to randomization (yes: 39.5%; no: 60.5%) and EDSS score at baseline (≤3.5: 83.3%; >3.5 16.7%). The mean age was 36.7 years and the majority of subjects (64.9%) were female. Most subjects were recruited in Europe with 50.6% from EU countries. Mean baseline EDSS score was 2.6, mean disease duration was 7.6 years and 97.4% were RRMS subjects. Mean pre-study 12-month relapse rate was 1.3, and 42.6% subjects had ≥1 Gd+T1 lesions on brain MRI. The treatment arms were generally balanced in terms of demographics and baseline disease characteristics (Tables 3 and 4).

1.3 Extent of Exposure

The mean treatment exposure (irrespective of interruptions) was 96.7 weeks in the ponesimod 20 mg arm and 97.5 weeks in the teriflunomide 14 mg arm. The cumulative exposure to ponesimod 20 mg was 1045 subject-years and was 1057 subject-years for teriflunomide 14 mg arm.

Efficacy endpoint: Ponesimod 20 mg reduced brain volume loss up to EOS by about 27% compared to teriflunomide 14 mg (BVL=−0.91% for ponesimod 20 mg vs. −1.25% for teriflunomide 14 mg, (0.34% difference, p<0.0001). The endpoint results are robust with similar results observed using a mixed model with linear time effect or using a repeated measurements ANOVA model (MMRM). Longitudinal brain volume measurements were derived from MRI scans by using Structural Image Evaluation, using Normalization, of Atrophy methodology (SIENA).

Using a mixed model with linear time effect (adjusted for stratification factors, presence/absence of GD+T1 lesions at baseline, and normalized brain volume at baseline), the LS mean percent change from baseline to Week 108 in brain volume was −0.91% in the ponesimod 20 mg group (n=436) and −1.25% in the teriflunomide 14 mg group (n=434). The LS mean difference (ponesimod 20 mg—teriflunomide 14 mg) was 0.34% (95% CLs: 0.17, 0.50; p<0.0001). The results are summarized in Table 6.

Results of the analysis using a repeated measurements ANOVA model (MMRM) were consistent with that described above with respect to the mixed model with linear time effect. The results are summarized in Table 7.

3.1 Summary of All Adverse Events

An overview of treatment emergent AEs (TEAEs) is presented in Table 8.

Overall, the proportion of subjects who experienced at least one TEAE was similar in both treatment arms (88.8% and 88.2% of subjects in the ponesimod 20 mg and the teriflunomide 14 mg arms, respectively).

The most common TEAEs in the ponesimod 20 mg arm were ALT increased (19.5%), nasopharyngitis (19.3%), headache (11.5%) and upper respiratory tract infection (10.6%). The most common TEAEs in the ponesimod 20 mg arm were ALT increased (19.5% vs 9.4% in the teriflunomide arm), nasopharyngitis (19.3% vs 16.8%), headache (11.5% vs 12.7%) and upper respiratory tract infections (10.6% vs 10.4%).

TEAEs leading to premature treatment discontinuation were reported in 8.7% of ponesimod 20 mg subjects compared to 6.0% of teriflunomide 14 mg subjects [see Table 9]. While the number of events was low, the difference in the type of AEs leading to treatment discontinuation was mainly driven by anticipated class effects on respiratory system and macular edema. No infections led to permanent study treatment discontinuation in the study.

There were two deaths reported in the study, one due to coronary artery insufficiency and one due to multiple sclerosis. Both deaths occurred in subjects receiving teriflunomide 14 mg.

The proportion of subjects who experienced at least one SAE was similar in both treatment arms (8.7% and 8.1% of subjects in the ponesimod 20 mg and the teriflunomide 14 mg arms, respectively).

An overview of AEs of special interest (AESIs) addressing anticipated risks of ponesimod is presented in Table 10. The most common AESIs were reported for category hepatobiliary disorders/liver enzyme abnormality (25.7% vs 14.5% in ponesimod 20 mg compared to teriflunomide 14 mg, respectively), followed by category hypertension (10.1% vs 9.0%), and pulmonary events (8.0% vs 2.7%).

The proportion of subjects who experienced ALT increase ≥3×ULN was higher in the ponesimod arm (17.3%) compared to teriflunomide (8.3%) whereas ALT increase >8×ULN was higher in the teriflunomide arm (2.1%) compared to ponesimod (0.7%). Based on the individual case review, most ALT/AST increases ≥3×ULN occurred as a single transient asymptomatic episode, resolving with continued treatment or after protocol mandated treatment discontinuation. All but one case of bilirubin increase ≥2×ULN occurred in subjects with pre-treatment bilirubin increases. One case of potential Hy's law occurred in a subject with pre-existing transaminase elevation (ALT>5×ULN), and the event fully resolved within 2 weeks after treatment discontinuation.

The incidence of treatment-emergent heart rate and rhythm (including hypotension) AESIs on Day 1 was higher in the ponesimod 20 mg arm (2.1%) than in the teriflunomide 14 mg arm (0.4%). See Table 10A. However, the overall incidence of first dose AESI on Day 1 was low (2.1%) in ponesimod. None of these events were serious nor led to permanent discontinuation of study treatment. Discharge criteria at 4 hours post-dose were met for ca. 99% of subjects. No 2nd or higher degree AV block was observed. ECG HR effect: nadir at 2 hours post-dose (siponimod—3-4 hours, fingolimod—around by 6 hours). Low incidence of low HR outliers (post-dose HR≤40 bpm), all 3 of them with a pre-treatment HR of <55 bpm, which is a known risk factor for post-dose bradycardia with S1P receptor modulators.

The mean heart rate reduction compared to pre-dose reached a maximum for ponesimod 20 mg at 2-hours post dose, −8.7 bpm compared to −1.7 bpm for teriflunomide 14 mg (FIG.2). There were 3 subjects with asymptomatic post-dose HR≤40 bpm in the ponesimod 20 mg arm (none on teriflunomide 14 mg); all of these subjects had a pre-treatment HR<55 bpm, which would require post-dose monitoring according to regulatory precedence of siponimod [Mayzent® USPI].

CONCLUSIONS

This study demonstrates the superior efficacy of ponesimod over teriflunomide in slowing brain volume loss.