WO2021214717A1

WO2021214717A1 - Dosing regimen for the use of siponimod for the treatment of acute respiratory distress syndrome

Info

Publication number: WO2021214717A1
Application number: PCT/IB2021/053348
Authority: WO
Inventors: Kasra SHAKERI-NEJAD; Eric Legangneux; Florian Von Raison
Original assignee: Novartis Ag
Priority date: 2020-04-23
Filing date: 2021-04-22
Publication date: 2021-10-28

Abstract

Provided is a dosing regimen for the administration of siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate, polymorph and/or mixtures thereof for treating respiratory distress syndrome (ARDS) resulting from infections that causes ARDS, such as viral infections, bacterial infections and fungal infections. In particular, the dosing regimen is for use in the treatment of ARDS from coronavirus (SARS-CoV) infections in corona virus disease patients, in particular SARS-CoV-2 infections in coronavirus disease 2019 (COVID-19) patients.

Description

DOSING REGIMEN FOR THE USE OF SIPONIMOD FOR THE TREATMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME

FIELD OF THE INVENTION

Provided is a dosing regimen forthe administration ofsiponimod, ora pharmaceutically acceptable salt, co-crystal, hydrate, solvate, polymorph and/or mixtures thereof for treating acute respiratory distress syndrome (ARDS) resulting from infections that cause ARDS, such as viral infections, bacterial infections and fungal infections. In particular, the dosing regimen is for use in the treatment of ARDS from coronavirus (SARS-CoV) infections in corona virus disease patients, in particular SARS-CoV-2 infections in coronavirus disease 2019 (COVID- 19) patients.

BACKGROUND OF THE INVENTION

Coronavirus disease 2019 (COVID-19) is an unprecedented challenge for physicians and healthcare systems worldwide. COVID-19 is a respiratory tract infection caused by a newly emergent coronavirus, SARS-CoV-2, that was first recognized in Wuhan, China, in December 2019. While most people with COVID-19 develop mild or uncomplicated illness, approximately 14% develop severe disease requiring hospitalization and oxygen support and 5% require admission to an intensive care unit. In severe cases, COVID-19 can be complicated by Acute Respiratory Distress Syndrome (ARDS). ARDS is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs (Fan, E; Brodie, D; Slutsky, AS (20 February 2018). "Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment". JAMA. 319 (7): 698-710. doi:10.1001 /jama.2017.21907. PMID 2946659). Symptoms include shortness of breath, rapid breathing, and bluish skin coloration (Fan et al 2018). The syndrome is associated with a mortality rate between 35 and 50% (Fan et al 2018) and survivors frequently face a decreased in quality of life (Matthay, MA; Zemans, RL; Zimmerman, GA; Arabi, YM; Beitler, JR; Mercat, A; Herridge, M; Randolph, AG; Calfee, CS (14 March 2019). "Acute respiratory distress syndrome". Nature Reviews. Disease Primers. 5 (1): 18. doi:10.1038/s41572-019-0069-0. PMC 6709677. PMID 30872586).

The identification of new treatment strategies that are effective in regulating the immune response, which characterizes the pathophysiology of ARDS, could further improve the outcome of patients who have a severe pulmonary manifestation from COVID-19. Excessive immune response towards SARS-CoV-2 infections may play a key role in inducing ARDS and even organ failure. Overall, virus particles first invade the respiratory mucosa and infect other cells, triggering a series of immune responses and the production of a cytokine storm in the body, which may be associated with the critical condition of COVID-19 patients. A subgroup of patients with severe COVID-19 might have a cytokine release syndrome (CRS). The secretion of large amounts of pro-inflammatory chemokines and cytokines (IL-1 , IL-6, IL- 8, IL-21 , TNF-b and MCP-1) is promoted in infected cells in response to SARS-CoV-2 infection. These chemokines and cytokines, in turn, recruit lymphocytes and leukocytes at the site of infection.

Sphingosine-1 -phosphate (S1 P) is a signal lysophospholipid that promotes cytokine synthesis and secretion. The S1 P receptor signaling pathways significantly inhibit the pathological damage induced by the host’s innate and adaptive immune responses, thereby reducing the cytokine storm caused by influenza virus infection. In mouse models of IAV infection, sphingosine-1- phosphate receptor 1 (S1 P1) signal transduction in respiratory endothelial cells modulates pathogenic inflammatory responses. Agonists or modulators targeting S1 P1 inhibit excessive recruitment of inflammatory cells, inhibit proinflammatory cytokines and chemokines, and reduce the morbidity and mortality of IAV. SARS-CoV-2 also mainly infects human lung epithelial cells and endothelial cells. Therefore, S1 P1 agonists may be potential therapeutic drugs for reducing cytokine and chemokine responses in those corona virus patients whose cells generated excessive immune responses.

Siponimod (BAF312) is a sphingosine-1 -phosphate (S1 P) receptor modulator and selectively targets 2 (S1 P1 and S1 P5) of the 5 known S1P receptors. Siponimod promotes a marked and long-lasting internalization and degradation of S1P1 receptors, thereby acting as a functional antagonist on S1 P1. This makes lymphoid cells unresponsive to S1P signaling, thus depriving them of their capacity to egress from lymphoid organs (lymph nodes and Peyer’s patches) and thereby preventing the recirculation of lymphocytes to blood and tissues. Similar to other drugs in this class, siponimod does not deplete lymphocytes but rather results in redistribution away from the intravascular compartment (Matloubian et al 2004). This effect results in a dose-dependent reduction of peripheral blood absolute lymphocyte count (ALC), including pro-inflammatory TH17 cells. Siponimod is approved for the treatment of multiple sclerosis.

Recently, potential beneficial effects of S1 P modulation have be hypothesized for patients with ARDS caused by coronavirus (SARS-CoV) infections, in particular SARS-CoV- 2 infections in coronavirus disease 2019 (COVID-19) patients. However, there remains a need for a new dosing regimen of siponimod to be used to treat ARDS, especially ARDS in SARS-CoV-2 infections in coronavirus disease 2019 (COVID-19) patients.

SUMMARY OF THE INVENTION

Provided is a dosing regimen forthe administration of siponimod, ora pharmaceutically acceptable salt, co-crystal, hydrate, solvate, polymorph and/or mixtures thereof for treating or preventing acute respiratory distress syndrome (ARDS) resulting from infections that causes ARDS, such as viral infections, bacterial infections and fungal infections. In particular, the dosing regimen is for use in the treatment or prevention of ARDS from coronavirus (SARS- CoV) infections in corona virus disease patients, in particular SARS-CoV-2 infections in coronavirus disease 2019 (COVID-19) patients.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" includes, but is not limited to, salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts provided herein include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts.

As used herein and unless otherwise indicated, the term "hydrate" means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term "solvate" means a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term "solvate" includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like). As used herein and unless otherwise indicated, the term "polymorph" means solid crystalline forms of a compound provided herein or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties.

As used herein, term "adverse effect" includes, but is not limited to gastrointestinal, renal and hepatic toxicities, leukopenia, increases in bleeding times due to, e.g., thrombocytopenia, and prolongation of gestation, nausea, vomiting, somnolence, asthenia, dizziness, teratogenicity, extra-pyramidal symptoms, akathisia, cardiotoxicity including cardiovascular disturbances, inflammation, male sexual dysfunction, and elevated serum liver enzyme levels. The term "gastrointestinal toxicities" includes but is not limited to gastric and intestinal ulcerations and erosions. The term "renal toxicities" includes but is not limited to such conditions as papillary necrosis and chronic interstitial nephritis.

The term "subject” includes human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, and reptiles. Except when noted, the terms “patient” or “subject” are used herein interchangeably.

As used herein, the terms “treat,” “treating,” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat,” “treating,” or “treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.

As used herein, the term “prevent”, “preventing" or “prevention” of any disease or disorder refers to the prophylactic treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

As used herein, and unless otherwise indicated, the terms "manage," "managing," and "management" encompass preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration ofthe disease ordisorder, or changing the way that a patient responds to the disease or disorder.

The term “therapeutically acceptable amount” or “therapeutically effective dose” interchangeably refers to an amount sufficient to effect the desired result (i.e., a reduction in tumorsize, inhibition oftumorgrowth, prevention of metastasis, inhibition orprevention of viral, bacterial, fungal or parasitic infection). In some embodiments, a therapeutically acceptable amount does not induce or cause undesirable side effects. In some embodiments, a therapeutically acceptable amount induces or causes side effects but only those that are acceptable by the healthcare providers in view of a patient’s condition. A therapeutically acceptable amount can be determined by first administering a low dose, and then incrementally increasing that dose until the desired effect is achieved. A “prophylactically effective dosage,” and a “therapeutically effective dosage,” of the molecules of the invention can prevent the onset of, or result in a decrease in severity of, respectively, disease symptoms, including symptoms associated with cancer. An “effective amount” fora particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the method, route and dose of administration and the severity of side effects (see, e.g., Maynard et al., A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, Fla., 1996; Dent, Good Laboratory and Good Clinical Practice, Urch Publ., London, UK, 2001).

The lUPAC name of siponimod is 1-{4-[(1 E)-N-{[4-cyclohexyl-3- (trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidine carboxylic acid and the compound is represented by the chemical structure according to Formula (I):,

Formula (I)

Siponimod is a selective sphingosine-1 -phosphate receptor modulator which is used in the treatment multiple sclerosis (MS).

WO 2004/103306 A2 relates to immunosuppressant compounds and processes for their production. Inter alia, a synthesis pathway for siponimod is described. In WO 2013/113915 A1 an alternative synthesis pathway for siponimod is described. Further, WO 2004/103306 A2 mentions that siponimod can generally be administered by any conventional administration route such as enterally, parentally, topically and in nasal or suppository form. However, said document does not describe any specific dose form.

Sphingosine-1 -phosphate (S1 P) receptors belong to a family of closely related, lipid- activated G-protein-coupled receptors. S1 P1 , S1 P2, S1 P3, S1 P4, and S1 P5 (also respectively termed EDG-1 , EDG-5, EDG-3, EDG-6 and EDG-8) are identified as receptors specific for S1 P. Certain S1 P receptors are associated with diseases mediated by lymphocyte interactions, for example, in transplantation rejections, autoimmune diseases, e.g. MS and inflammatory myopathies, inflammatory diseases, infectious diseases and cancer.

Siponimod acts as a selective modulator of two of the five sphingosine-1 -phosphate (S1P) receptors: S1 P1 and S1P5. T cells selectively require S1 P1 activation for emigration from the thymus, and both T- and B cells require this receptor for egress from peripheral lymphoid organs ( Matloubian et al. 2004, Brinkmann et ai 2004). Pre-clinical data from mice with defective expression of S1 P1 in lymphocytes propose an obligatory role of S1 P1 in the egress of lymphocytes from lymphatic tissues.

Siponimod is a second-generation S1 P receptor modulator that reduces peripheral lymphocyte counts approximately 4 - 6 hours (h) after the first dose. The half-life of siponimod is approximately 30 hours, which allows reversal of pharmacodynamic effects and recovery of the baseline lymphocyte counts within a week after treatment withdrawal. Siponimod's mode of action is believed to include S1 P1 -mediated prevention of effector lymphocyte recirculation from lymphatic tissue to sites of inflammation, such as the central nervous system (CNS). In addition, there may be direct beneficial effects in the CNS mediated by S1 P1 and/or S1P5. Siponimod readily crosses the blood brain barrier and evidence from preclinical models suggests that siponimod may target S1 P1 and S1P5 on neurons, astrocytes and oligodendrocytes and may modulate neurobiological processes (Choi et al 2011). Thus, siponimod may display additional beneficial activities in the CNS.

The pharmaceutically acceptable salts can e.g. be obtained by the reaction of siponimod with an acid. Examples of pharmaceutically acceptable salts of the compound of siponimod include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, as well as salts with organic acids such as acetic acid, maleic acid, benzoic acid, citric acid, malic acid, as well as salts with sulfonic acid, such as methanesulfonicacid orbenzenesulfonic acid, or, when appropriate, salts with metals, such as sodium, potassium, calcium and aluminium, salts with amines, such as trimethylamine, and salts with dibasic amino acids, such as lysine.

The compounds and salts of the combination of the pharmaceutical composition encompass hydrate and solvate forms. In a preferred pharmaceutical composition siponimod is in the form of an acid addition product with fumaric acid. In a more preferred pharmaceutical composition siponimod is in the form of a co-crystal.

Generally, a co-crystal can be referred to as crystalline material composed of two or more different molecules in the same lattice, wherein these two or more molecules are nonvolatile. Co-crystals can be preferably be distinguished from salts because unlike salts their components are in a neutral state and interact non-ionically. In particular preferred pharmaceutical compositions, siponimod is in the form of a cocrystal of siponimod with fumaric acid, hereinafter also referred to as (1-{4-[(1 E)-N-{[4- cyclohexyl-3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid-fumaric acid co-crystal.

The ratio of fumaric acid, i.e. (2E)-But-2-enedioic acid, to 1-{4-[(1 E)-N-{[4-cyclohexyl- 3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid can e.g. range from 0.3 to 0.7, preferably it can be about 0.5.

The lUPAC name of the preferred co-crystal of siponimod with fumaric acid is (2E)- But-2-enedioic acid - 1-({4-[(1E)-N-{[4-cyclohexyl-

3(trifluoromethyl)phenyl]methoxy}ethanimidoyl]-2-ethylphenyl}methyl)azetidine-3-carboxylic acid (1 :2).

In still more preferred pharmaceutical compositions, siponimod is used as 1-{4-[(1 E)- N-{[4-cyclohexyl-3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3- azetidinecarboxylic acid-fumaric acid co-crystal in polymorphic form A having an X-ray powder diffraction pattern with specific peaks at 6.9, 10.1 , 10.6, 12.1 , 17.5 18.1 and 20.7° (20).

In still more preferred pharmaceutical compositions, siponimod is used as 1-{4-[(1 E)- N-{[4-cyclohexyl-3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3- azetidinecarboxylic acid-fumaric acid co-crystal in polymorphic form A having an X-ray powder diffraction pattern (XRPD pattern) with specific peaks at 6.9, 10.1 , 10.6, 12.1 , 17.5 18.1 and 20.7° (20).

In alternatively preferred pharmaceutical compositions, siponimod is used in the free form. Unless otherwise mentioned within the present application the amounts orweight-% of siponimod are based on the amount of siponimod in free form. That is, if siponimod is present in form of a salt, the amount of the free from has to be calculated accordingly. For example, if siponimod is present in the form of its HCI salt in an amount of 1 .00 g, this amount corresponds to circa 0.93 of free siponimod.

In further pharmaceutical compositions, the parenteral formulation can comprise further APIs, preferably APIs suitable to enhance the effect of the parenteral formulation. Further APIs may comprise other drugs, e.g. immunosuppressant(s), steroids(s), such as prednisolone, methylprednisolone dexamethasone, hydrocortisone and the like or nonsteroidal anti-inflammatory agent(s). The dosing regimen of a combination treatment may depend on the effectiveness and site of action of each active agent as well as synergistic effects between the agents used for combination therapy.

In alternative preferred pharmaceutical compositions, siponimod is used as the sole active pharmaceutical ingredient in the formulation and/or the treatment according to the present disclosure. Dosing Regimen

The dosing regimens with siponimod rapidly attenuate maladjusted immune responses while sparing memory immune responses and thus has relatively low risk of infections.

The well-characterized transient dose-dependent negative chronotropic effects of siponimod on heart rate (HR) and the effects on cardiac conduction are mediated via S1 P1 receptor agonism and subsequent GIRK channel activation. With continued dosing S1 P1 receptor internalization and down-modulation results in desensitization to and consequently disappearance of HR effects and effects on atrioventricular (AV) conduction over time despite continued exposure with higher plasma concentrations. The HR effects of siponimod during initial dosing are a result of two sequential processes: an initial direct S1 P1 agonism of siponimod (HR reduction) with subsequent S1P1 receptor internalization over time (desensitization to HR effects).

A specifically designed dose titration study demonstrated that the effects of siponimod on HR and AV conduction observed under non-titrated conditions could be attenuated by dose titration. One of the two dose titration regimens investigated in the dose titration study was employed in clinical Phase 2 and 3 studies in MS patients and in all subsequent multiple dose Clinical Pharmacology studies, in which it efficiently mitigated the known effects on HR and AV conduction. The same dose titration is used to attenuate initial negative chronotropic and atrioventricular (AV) conduction effects of siponimod in the clinic and is described in the MAYZENT prescribing information.

Data from Phase 1 Clinical Pharmacology studies in healthy subjects (Figure 3-3) and Phase 2 and 3 studies in MS patients show that the largest HR decrease occurs on the first day of dosing, with smaller HR reductions on subsequent days of dosing. This suggests that most of the desensitization due to S1 P1 receptor internalization and down-modulation is achieved already on the first day of dosing and is largely complete by Day 3 of the oral dose titration (siponimod SCP and SCS).

A more enhanced understanding of the mechanisms involved in the negative chronotropic and AV conduction effects of siponimod and their desensitization over time suggest that the observed HR effects of siponimod are rather correlated to the rate at which Cmax is achieved (slope of the plasma concentration-time profile) than to plasma AUC or Cmax only (“slope hypothesis”). Any efficacious dose titration scheme would therefore need to find the optimal balance in: a. not inducing initial HR effects of clinical relevance (due to steep initial increase in plasma concentrations and direct S1 P agonism on non-internalized/down-modulated S1 P1 receptors) whilst b. still producing sufficiently high siponimod plasma concentrations to desensitize the S1 P1 receptors within the first few hours prior to reaching the targeted maintenance dose level.

Considering the existing clinical evidence and based on the considerations described above new rapid oral dose titration regimens were developed for the acute and immediate setting of COVID-19-associated ARDS with the aim to: a. achieve a robust reduction in absolute lymphocyte count already within the first hours of treatment initiation and to reach therapeutic (2 mg) dose levels and exposures within the first 24 h (i.e. by Day 2 of treatment), whilst b. keeping the expected effects on heart rate and AV conduction at treatment initiation manageable in the intended patient population in an intensive care treatment setting.

Examples of dosing regimens of the disclosure are:

Option 1 : 0.5 mg of siponimod on Day 1 and 2.0 mg of siponimod per day thereafter. In a preferred embodiment, 0.5 mg of siponimod is administered on Day 1 and 2.0 mg of siponimod is administered once per day on Day 2 through Day 14; and then stopping administration of siponimod on Day 15.

Option 2: 0.5 mg siponimod on Day 1 ; 1 .0 mg siponimod at least about 8 hours to at most about 12 hours thereafter; and 2.0 mg siponimod per day thereafter. In a preferred embodiment, 0.5 mg siponimod is administered on Day 1 ; 1.0 mg siponimod is administered on Day 1 at least about 8 hours to at most about 12 hours thereafter; 2.0 mg of siponimod is administered per day on Day 2 through Day 14; and then stopping administration of siponimod on Day 15.

Option 3: 0.25 mg siponimod on Day 1 ; a second 0.25 mg dose at least about 5 hours to at most 6 hours thereafter; 1.0 mg dose of siponimod at least about 5 hours to at most 6 hours after the second 0.25 mg dose; and 2.0 mg siponimod per day thereafter. In a preferred embodiment, 0.25 mg of siponimod is administered on Day 1 ; a second 0.25 mg dose of siponimod is administered on Day 1 at least about 5 hours to at most 6 hours thereafter; a 1 .0 mg dose of siponimod is administered on Day 1 at least about 5 hours to at most 6 hours after the second 0.25 mg dose; 2.0 mg siponimod is administered once per day on Day 2 through Day 14; and then administration of siponimod is stopped on Day 15.

The above dosing regimens are useful in treating acute respiratory distress syndrome (ARDS) resulting from a pathogenic infection. Such infections include, but are not limited to, viral, bacterial and fungal infections. Viral infections include infections from influenza and coronovirus, including betacoronavirus, SARS-CoV, SARS-CoV-2, including infections from SARS-CoV-2 infections in coronavirus disease 2019 (COVID-19) patients, and MERS-CoV infections. Treatment with siponimod can last more than 5 days, preferably 7 to 60 days, 7 to 28 days or 14 days total. The efficacy of such dosing regimens can be tested through, for example, PK/PD simulations or clinical trials. In one embodiment ADRS is treated, in another embodiment ADRS is prevented.

Also provided herein is a method for the treatment or prevention of acute respiratory distress syndrome (ARDS) resulting from infections that cause ARDS, such as viral infections, bacterial infections and fungal infections, comprising administration of siponimod or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate, polymorph and/or mixtures thereof, through one of the above dosage regimens to patient in need thereof. In a preferred embodiment, ADRS is resulting from a viral infection such as SARS-CoV-2, including infections in coronavirus disease 2019.

One embodiment provides for a method of treatment or prevention of ARDS through the administration of siponimod, to a patient in need thereof, wherein 0.5 mg of siponimod is administered on Day 1 and 2.0 mg of siponimod is administered once per day thereafter. In a preferred embodiment, 0.5 mg of siponimod is administered on Day 1 and 2.0 mg of siponimod is administered once per day on Day 2 through Day 14; and then administration of siponimod is stopped on Day 15. In a preferred embodiment ADRS is resulting from infections that cause ARDS, such as viral infections, bacterial infections and fungal infections. In a preferred embodiment, ADRS is resulting from a viral infection such as SARS-CoV-2, including infections in coronavirus disease 2019.

Another embodiment provides for a method of treatment or prevention of ARDS through the administration of siponimod to a patient in need thereof wherein 0.5 mg siponimod is administered on Day 1 ; 1 .0 mg siponimod is administered at least about 8 hours to at most about 12 hours thereafter; and 2.0 mg siponimod is administered per day thereafter. In a preferred embodiment, 0.5 mg siponimod is administered on Day 1 ; 1.0 mg siponimod is administered on Day 1 at least about 8 hours to at most about 12 hours thereafter; 2.0 mg of siponimod is administered per day on Day 2 through Day 14; and then administration of siponimod is stopped on Day 15. In a preferred embodiment, ADRS is resulting from infections that cause ARDS, such as viral infections, bacterial infections and fungal infections. In a preferred embodiment, ADRS is resulting from a viral infection such as SARS-CoV-2, including infections in coronavirus disease 2019.

Another embodiment provides for a method of treatment or prevention of ARDS through the administration of siponimod to a patient in need thereof wherein 0.25 mg siponimod is administered on Day 1 ; a second 0.25 mg dose is administered at least about 5 hours to at most 6 hours thereafter; 1.0 mg dose of siponimod is administered at least about 5 hours to at most 6 hours after the second 0.25 mg dose; and 2.0 mg siponimod is administered per day thereafter. In a preferred embodiment, 0.25 mg of siponimod is administered on Day 1 ; a second 0.25 mg dose of siponimod is administered on Day 1 at least about 5 hours to at most 6 hours thereafter; a 1.0 mg dose of siponimod is administered on Day 1 at least about 5 hours to at most 6 hours after the second 0.25 mg dose; 2.0 mg siponimod is administered once per day on Day 2 through Day 14; and then administration of siponimod is stopped on Day 15. In a preferred embodiment ADRS is resulting from infections that cause ARDS, such as viral infections, bacterial infections and fungal infections. In a preferred embodiment, ADRS is resulting from a viral infection such as SARS-CoV-2, including infections in coronavirus disease 2019.

In a preferred embodiment siponimod is administered orally.

In a preferred embodiment siponimod is in the form of a co-crystal of siponimod with fumaric acid, hereinafter also referred to as (1-{4-[(1 E)-N-{[4-cyclohexyl-3- (trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid-fumaric acid co-crystal.

All the aforementioned embodiments relating to the methods of treatment of certain diseases with particular dosing regimens are equally applicable to siponimod for use in the treatment of certain diseases with certain dosing regimens according to the present disclosure; use of siponimod in the manufacture of a medicament for the treatment of certain diseases with particular dosing regimens according to the present disclosure; the use of siponimod for the treatment of certain diseases with particular dosing regimens according to the present disclosure; and a pharmaceutical composition comprising siponimod, and one or more pharmaceutically acceptable carriers, for use in the treatment of certain diseases with particular dosing regimens according to the present disclosure.

Cardiac effects

Cardiac effects of siponimod at treatment initiation include negative chronotropic effects such as heart rate reduction, transient bradycardia, and sinus pauses (RR interval greater than 2 seconds) and negative dromotropic effects on AV conduction, including AV blocks (first degree AV blocks (e.g. PR intervals greater than 0.2 seconds) and second degree AV blocks).

The dosage regimens provided herein are optimal due to the less pronounced and more manageable cardiac profile on Day 1 while still providing rapid ALC reduction within the first hours of treatment of approximately 50% of that expected with the target therapeutic maintenance dose of 2 mg.

These considerations are supported by heart rate results and lymphocyte count results from the single ascending dose study in healthy subjects investigating single oral siponimod doses of 0.1 to 75 mg. The results demonstrate that the mean HR reduction after siponimod 0.3 mg single oral doses is comparable to that of placebo while the placebo-adjusted mean HR reduction after a 1 mg single oral dose is around 8 bpm (Table 1). Since the HR reduction shows a dose-dependent behavior, the HR effect of the 0.5 mg starting dose on Day 1 (Options 1 and 2) is expected to result in an effect close to the one observed with a 0.3 mg dose and is therefore considered to be manageable in the intended patient population in an intensive care treatment setting. In addition, the dose increase from 0.5 mg (Day 1) to 2 mg (Day 2 and onwards) is not expected to result in pronounced cardiac effects as most of the S1 P1 receptor internalization is achieved already on the first day of dosing.

Table 1 Emax (0-24) heart rate Day 1

Treatment mean (SD) CV median (min, max)

Placebo

53.7 (13.02)

74.24

55.5 (15,71)

BAF3120.1 mg (L) 56.1 (6.11) 10.89 57.0 (47,66)

BAF3120.3 mg (L)

56.0 (6.97)

12.45

56.0 (48.67)

BAF312 1.0 mg (L) 46.0 (7.54) 16.39 44.0 (35,56)

BAF312 2.5 mg

44.3 (9.20)

20.73

43.5 (30,58)

BAF3125.0 mg (C) 42.9 (4.39) 10.24 43.5 (.35,48)

BAF312 10 mg (C) 44.3 (6.90) 15.60

44.5 (32,56)

BAF312 17.5 mg (C) 43.9 (3.04) 6.94 43.0 (40,48)

BAF31225 mg (C)

37.5 (5.29)

14.11

37.0 (32.48)

BAF31275 mg (C) 35.1 (7.36) 20.95 34.5 (24,47)

L = Liquid, C= Capsule, CV = coefficient of variation, Emax (0-24) = maximum effect 0-24 h post dose

Source: CBAF312A2101 CSR - Table 14.2-2.13 Statistics analysis for heart rate summary endpoints of Day 1 .

Effects on peripheral lymphocytes

Siponimod promotes a marked and long-lasting internalization and degradation of S1 P1 receptors, thereby acting as a functional antagonist on S1P1. This makes lymphoid cells unresponsive to S1 P signaling, thus depriving them of their capacity to egress from lymphoid organs (lymph nodes and Peyer’s patches) and thereby preventing the recirculation of lymphocytes to blood and tissues and leading to redistribution away from the intravascular compartment ( atloubian et al 2004).

Lymphocyte results from the single ascending dose study in healthy subjects investigating single oral siponimod doses of 0.1 to 75 mg demonstrate that an initial oral dose of 0.5 mg is expected to induce an approximately 35% reduction in circulating lymphocytes corresponding to an expected 70-80% reduction associated with the target therapeutic maintenance dose of 2 mg (Day 2 to Day 14). This means that by using a 0.5 mg initial dose on Day 1 a robust lymphocyte reducing effect can be established within 4 to 6 h post dose which corresponds to approximately 50% of that of a 2 mg dose (Tables 2 and 3). This rapid onset of lymphocyte effects is of particular importance in an acute setting as in the intended population.

Table 2: Median (90% prediction interval) simulated trough siponimod plasma concentration and trough lymphocyte count at steady state in healthy subjects by dose

0.1 1.05 (0.54, 1.75) 1.73 (1.07, 2.60)

0.25 2.66 (

1.43

0.5 5.18 (2.62, 8.80) 1.21 (0.660, 1.90)

Source: CBAF312A-Phase 3-PopPKPD - Table 5-17 and SCP Table 3-32

Table 3 % Emax (0-24) heart rate on Day 1

Treatment Adjusted mean Treatment 90% Cl difference

Placebo

22.896

BAF3120.1 mg (L) 31.903 9.007 (-5.122, 23.136)

BAF3120.3 mg (L)

32.217

9.321

( 6.398. 25.039)

BAF312 1.0 mg (L) 53.861 30.965

BAF312 2.5 mg

71.761

48.865

BAF3125.0 mg (C) 78.950 56.054

BAF312 10 mg (C)

85.076

62.180

BAF312 17.5 mg (C) 82.353 59.457

BAF312 25 mg (C)

85.625

62.731

BAF31275 mg (C) 88.114 65.217

L = Liquid, C= Capsule, CV = coefficient of variation, %Emax (0-24) = maximum effect rate 0-24 h post dose Source: CBAF312A2101 CSR - Table 14.2-2.6 Statistics analysis for lymphocyte summary endpoints of Day 1 .

Formulations

In one embodiment the drug product comprising siponimod is a solid form, e.g., tablet, suitable for oral administration.

Pharmaceutical composition containing siponimod for oral administration

Siponimod is available as film-coated tablets for oral administration. Oral dosage forms of siponimod are known in the art. Tablets containing siponimod, for example, are described in WO 2012/093161 A1 and WO 2015/155711 A1. Further, WO 2007/021666 A2 relates to oral liquids of S1 P- receptor agonists.

Examples of oral solid compositions of siponimod are the film-coated tablets provided hereinafter:

Table 4 Qualitative composition of siponimod film-coated tablets

Tablets (composition 1) Tablets (composition 2)

Strengths: 0.1 mg, 0.25 mg, 1 mg, 4 mg, 5 Strengths: 0.25 mg, 0.5 mg, 1 mg, 2 mg mg

Tablet core: Tablet core:

Siponimod drug substance Siponimod drug substance Lactose monohydrate (Ph. EurVNF) Lactose monohydrate (Ph. Eur./NF) Microcrystalline cellulose/ (Ph. Eur./NF) Microcrystalline cellulose/ (Ph. Eur./NF)

Crospovidone (Ph. Eur./NF) Crospovidone (Ph. Eur./NF)

Magnesium stearate (Ph. Eur./NF) Glyceryl behenate (Ph. Eur./NF)

Silica, colloidal anhydrous/ Silica, colloidal anhydrous/

Colloidal silicon dioxide (Ph. Eur./NF) Colloidal silicon dioxide (Ph. Eur./NF)

Film-coat: Film-coat:

Polyvinyl alcohol- partially hydrolyzed (Ph. Polyvinyl alcohol- partially hydrolyzed (Ph. Eur./USP) Eur./USP)

Titanium dioxide (Ph. Eur./USP) Titanium dioxide (Ph. Eur./USP)

Talc (Ph. Eur./USP) Talc (Ph. Eur./USP)

Lecithin (soya) (NF) Lecithin (soya) (NF)

Xanthan gum (Ph. Eur./NF) Xanthan gum (Ph. Eur./NF)

The film-coated tablets are packed in high density polyethylene (HDPE) bottles with induction seals (with or without a desiccant). They may also be packaged in polyvinylchloride/ polychlorotrifluoroethylene-Alu or Alu-alu blisters. A further example of an oral solid composition in the form of a 2 mg tablet is provided hereinafter.

Table 5 Siponimod 2 mg Tablets

° Removed during processing. Solution made with 20% solid concentration.

Embodiments

Embodiment 1 . A method of administering siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 and 2.0 mg siponimod once per day thereafter.

Embodiment 2. A method of embodiment 1 , wherein siponimod or a pharmaceutically acceptable, salt, co-crystal, hydrate, solvate or polymorph thereof is administered orally.

Embodiment 3. The method of any one of embodiments 1 or 2, wherein siponimod is in the form of a co-crystal of siponimod with fumaric acid, referred to as (1-{4-[(1 E)-N-{[4-cyclohexyl- 3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid-fumaric acid co-crystal.

Embodiment 4. The method of embodiment 3, wherein siponimod in the form of a co-crystal of siponimod with fumaric acid is (2E)-But-2-enedioic acid -1-({4-[(1 E)-N-{[4-cyclohexyl- 3(trifluoromethyl)phenyl]methoxy}ethanimidoyl]-2-ethylphenyl}methyl)azetidine-3-carboxylic acid (1 :2).

Embodiment 5. The method of any one of embodiments 1-4, wherein the subject is suffering from acute respiratory distress syndrome (ARDS).

Embodiment 6. The method of any one of embodiments 1-5, wherein the subject is suffering from a coronavirus infection.

Embodiment 7. The method of any one of embodiments 1-6, wherein the subject is suffering from a betacoronavirus infection.

Embodiment 8. The method according to any one of embodiments 1-7 wherein the subject is suffering from SARS-CoV, SARS-CoV-2 or MERS-CoV infection.

Embodiment 9. The method according to any one of embodiments 1-8 wherein the subject is suffering from COVID-19 caused by a SARS-CoV-2 infection.

Embodiment 10. The method of any one of embodiments 1-9, wherein siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, is administered to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 ; 2.0 mg siponimod once per day on Day 2 through Day 14; and then stopping administration of siponimod on Day 15.

Embodiment 11 . A method of administering siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 ; 1 .0 mg siponimod at least about 8 hours to at most about 12 hours thereafter; and 2.0 mg siponimod once per day thereafter.

Embodiment 12. The method according to embodiment 11 , wherein siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, is administered to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 ; 1 .0 mg siponimod on Day 1 at least about 8 hours to at most about 12 hours thereafter; 2.0 mg of siponimod once per day on Day 2 through Day 14; and then stopping administration of siponimod on Day 15. Embodiment 13. A method of administering siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, to a subject in need thereof .comprising administering 0.25 mg siponimod on Day 1 ; a second 0.25 mg dose of siponimod at least about 5 hours to at most 6 hours thereafter; a 1.0 mg dose of siponimod at least about 5 hours to at most 6 hours after the second 0.25 mg dose of siponimod; and 2.0 mg siponimod once per day thereafter.

Embodiment 14. The method according to embodiment 13, wherein siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, is administered to a subject in need thereof comprising administering a 0.25 mg of siponimod on Day 1 ; a second 0.25 mg dose of siponimod on Day 1 at least about 5 hours to at most 6 hours thereafter; a 1.0 mg dose of siponimod on Day 1 at least about 5 hours to at most 6 hours after the second 0.25 mg dose; a 2.0 mg siponimod dose of siponimod once per day on Day 2 through Day 14; and then stopping administration of siponimod on Day 15.

Embodiment 15. The method of any one of embodiments 11-14, wherein siponimod or a pharmaceutically acceptable, salt, co-crystal, hydrate, solvate or polymorph thereof is administered orally.

Embodiment 16. The method of any one of embodiments 11-15, wherein siponimod is in the form of a co-crystal of siponimod with fumaric acid, referred to as (1-{4-[(1 E)-N-{[4-cyclohexyl- 3-(trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid-fumaric acid co-crystal.

Embodiment 17. The method of embodiment 16, wherein siponimod in the form of a co-crystal of siponimod with fumaric acid is (2E)-But-2-enedioic acid -1-({4-[(1 E)-N-{[4-cyclohexyl- 3(trifluoromethyl)phenyl]methoxy}ethanimidoyl]-2-ethylphenyl}methyl)azetidine-3-carboxylic acid (1 :2).

Embodiment 18. The method of any one of embodiments 11-17, wherein the subject is suffering from acute respiratory distress syndrome (ARDS).

Embodiment 19. The method of any one of embodiments 11-18, wherein the subject is suffering from a coronavirus infection.

Embodiment 20. The method of any one of embodiments 11-19, wherein the subject is suffering from a betacoronavirus infection.

Embodiment 21 . The method according to any one of embodiments 11 -20 wherein the subject is suffering from a SARS-CoV, SARS-CoV-2 or MERS-CoV infection. Embodiment 22. The method according to any one of embodiments 11-21 wherein the subject is suffering from COVID-19 caused by a SARS-CoV-2 infection.

Examples

Example 1 : Clinical trials for testing a dosing regimen for use in patients having Covid-19, in particular Covid-19 with acute respirtory distress syndrom.

Patients are recruited in accordance with the following criteria:

1. Patients over the age of 18 years old.

2. Clinically diagnosed with Covid-19

3. Hosptitalized with Covid-19 Exclusion criteria may include:

1. Pregnant women

2. Patients having a diagnosis of macular edma

3. Patients having 31*3 CYP2C9 genotype

4. Patients with myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class lll/IV heart failure

5. Patients having a presence of obitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker

6. Patients with significant QT prolongation (QTc greater than 500 msec)

7. Patients with arrhythmias requiring treatment with Class la or Class III anti-arrhythmic drugs

8. Pateints having a recent herpes zoster infection

9. Patients with ALT or AST three-fold higher than upper limit of normal (ULN)

Patients are dosed with siponimod according to any of the dosage regimens described above. Primary outcome measure is change in severity of pneumonia or ARDS through, for example, lung x-ray or CT scan.

Claims

We claim:

1. A method of administering siponimod, or a pharmaceutically acceptable salt, cocrystal, hydrate, solvate or polymorph thereof, to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 and 2.0 mg siponimod once per day thereafter.

2. A method of claim 1 , wherein siponimod or a pharmaceutically acceptable, salt, cocrystal, hydrate, solvate or polymorph thereof is administered orally.

3. The method of any one of claims 1 or 2, wherein siponimod is in the form of a cocrystal of siponimod with fumaric acid, referred to as (1-{4-[(1 E)-N-{[4-cyclohexyl-3- (trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid- fumaric acid co-crystal.

4. The method of claim 3, wherein siponimod in the form of a co-crystal of siponimod with fumaric acid is (2E)-But-2-enedioic acid -1-({4-[(1 E)-N-{[4-cyclohexyl- 3(trifluoromethyl)phenyl]methoxy}ethanimidoyl]-2-ethylphenyl}methyl)azetidine-3- carboxylic acid (1 :2).

5. The method of any one of claims 1-4, wherein the subject is suffering from acute respiratory distress syndrome (ARDS).

6. The method of any one of claims 1-5, wherein the subject is suffering from a coronavirus infection.

7. The method of any one of claims 1-6, wherein the subject is suffering from a betacoronavirus infection.

8. The method according to any one of claims 1-7 wherein the subject is suffering from SARS-CoV, SARS-CoV-2 or MERS-CoV infection.

9. The method according to any one of claims 1-8 wherein the subject is suffering from COVID-19 caused by a SARS-CoV-2 infection.

10. The method of any one of claims 1-9, wherein siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, is administered to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 ; 2.0 mg siponimod once per day on Day 2 through Day 14; and then stopping administration of siponimod on Day 15.

11. A method of administering siponimod, or a pharmaceutically acceptable salt, cocrystal, hydrate, solvate or polymorph thereof, to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 ; 1 .0 mg siponimod at least about 8 hours to at most about 12 hours thereafter; and 2.0 mg siponimod once per day thereafter.

12. The method according to claim 11 , wherein siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, is administered to a subject in need thereof comprising administering 0.5 mg siponimod on Day 1 ; 1 .0 mg siponimod on Day 1 at least about 8 hours to at most about 12 hours thereafter; 2.0 mg of siponimod once per day on Day 2 through Day 14; and then stopping administration of siponimod on Day 15.

13. A method of administering siponimod, or a pharmaceutically acceptable salt, cocrystal, hydrate, solvate or polymorph thereof, to a subject in need thereof .comprising administering 0.25 mg siponimod on Day 1 ; a second 0.25 mg dose of siponimod at least about 5 hours to at most 6 hours thereafter; a 1.0 mg dose of siponimod at least about 5 hours to at most 6 hours afterthe second 0.25 mg dose of siponimod; and 2.0 mg siponimod once per day thereafter.

14. The method according to claim 13, wherein siponimod, or a pharmaceutically acceptable salt, co-crystal, hydrate, solvate or polymorph thereof, is administered to a subject in need thereof comprising administering a 0.25 mg of siponimod on Day 1 ; a second 0.25 mg dose of siponimod on Day 1 at least about 5 hours to at most 6 hours thereafter; a 1.0 mg dose of siponimod on Day 1 at least about 5 hours to at most 6 hours afterthe second 0.25 mg dose; a 2.0 mg siponimod dose of siponimod once per day on Day 2 through Day 14; and then stopping administration of siponimod on Day

15.

15. The method of any one of claims 11-14, wherein siponimod or a pharmaceutically acceptable, salt, co-crystal, hydrate, solvate or polymorph thereof is administered orally.

16. The method of any one of claims 11-15, wherein siponimod is in the form of a cocrystal of siponimod with fumaric acid, referred to as (1-{4-[(1 E)-N-{[4-cyclohexyl-3- (trifluoromethyl)benzyl]oxy}ethanimidoyl]-2-ethylbenzyl}-3-azetidinecarboxylic acid- fumaric acid co-crystal.

17. The method of claim 16, wherein siponimod in the form of a co-crystal of siponimod with fumaric acid is (2E)-But-2-enedioic acid -1-({4-[(1 E)-N-{[4-cyclohexyl- 3(trifluoromethyl)phenyl]methoxy}ethanimidoyl]-2-ethylphenyl}methyl)azetidine-3- carboxylic acid (1 :2).

18. The method of any one of claims 11-17, wherein the subject is suffering from acute respiratory distress syndrome (ARDS).

19. The method of any one of claims 11-18, wherein the subject is suffering from a coronavirus infection.

20. The method of any one of claims 11-19, wherein the subject is suffering from a betacoronavirus infection.

21 . The method according to any one of claims 11-20 wherein the subject is suffering from a SARS-CoV, SARS-CoV-2 or MERS-CoV infection.

22. The method according to any one of claims 11-21 wherein the subject is suffering from COVID-19 caused by a SARS-CoV-2 infection.