WO2021158844A1

WO2021158844A1 - Treatment and dosing regimen for s1p receptor modulator

Info

Publication number: WO2021158844A1
Application number: PCT/US2021/016704
Authority: WO
Inventors: Jeffrey R. Gardner
Original assignee: Argentum Pharmaceuticals Llc
Priority date: 2020-02-07
Filing date: 2021-02-05
Publication date: 2021-08-12

Abstract

The present invention relates to a kit including a test, vaccine, and/or one or more doses of an S1P receptor modulator or agonist in the course for the treatment of patients suffering from an inflammatory or autoimmune disease or disorder, for example multiple sclerosis (MS). By administering a S1P receptor modulator or agonist using kits according to the present application, it is possible to accelerate treatment for patients having barriers to receiving effective or adequate medical treatment.

Description

TREATMENT AND DOSING REGIMEN FOR S1P RECEPTOR MODULATOR

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 62/971 ,721, filed February 7, 2020, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to kits for an S1 P receptor modulator or agonist for the treatment of patients suffering from an inflammatory or autoimmune disease or disorder, for example multiple sclerosis (MS).

BACKGROUND

[0003] Multiple sclerosis is an autoimmune disorder or disease which results in the demyelination of the insulating cover nerve cells in the brain and spinal cord. The damage disrupts the ability of parts of the central nervous system to transmit and receive signals. The disruption in signaling often causes physical, mental, and psychiatric problems. While the underlying mechanism of action remains unknown, multiple sclerosis is thought to be caused by destruction by the immune system of either myelin itself or myelin-producing cells.

[0004] Multiple sclerosis is the chief cause of neurological disability in young adults and the most common demyelinating disorder of the central nervous system. Available therapies such as interferon-b and glatiramer acetate have modest efficacy and marginal effects on the progression of disability. These biological agents are administered parenterally and are associated, e.g., with injection site reactions and pyretic symptoms, such as flu-like symptoms.

[0005] Sphingosine-1 -phosphate (S1 P) receptor modulators are a class of drugs used as immunomodulators, for example for the treatment of autoimmune disorders or diseases such as multiple sclerosis (MS). Suphingosine-1-phospate (S1 P) is a signaling sphingolipid which binds with several S1 P receptors, e.g. S1P Receptor 1 (S1 PR1 ) to S1 P Receptor 5 (S1 PR5). In particular, it is believed S1 P interaction with S1 PR1 (a G-protein-coupled S1 P receptor) is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels.

[0006] Several S1 P receptor modulators impact the ability of S1 P to bind with S1 PR1 through S1PR8. In particular, based on interaction with S1 PR1 , it is believed such compounds modulate the release of certain lymphoid immune cells, which can ultimately reach the central nervous system. For example, Fingolimod is believed to cause the internalization of S1 P receptors, including S1 PR1 , which sequesters lymphocytes in the lymph nodes, preventing them from moving to the central nervous system and causing a relapse of multiple sclerosis. Fingolimod efficacy in the treatment of multiple sclerosis (MS) has been shown in humans (e.g. as described in “FTY720 therapy exerts differential effects on T call subsets in multiple sclerosis”. Mehling M, et al. , Neurology. 2008 Oct. 14; 71 (16): 1281 -7 ; and “Oral fingolimod (FTY720) for relapsing multiple sclerosis”. Kappos L, Antel J, Comi G, Montalban X, O'Connor P, Polman C FI, Flaas T, Korn A A, Karisson G, Radue E W; FTY720 D2201 Study Group. N Engl J Med. 2006 Sep. 14; 355(11): 1124-40.).

[0007] Varicella zoster virus (VZV) is a human virus belonging to the a- herpesvirus family. VZV is present worldwide and is highly infectious. Primary infection leads to acute varicella or “chickenpox,” usually from exposure either through direct contact with a skin lesion or through airborne spread from respiratory droplets. (Sawyer MH, Chamberlin CJ, Wu YN, Aintablian N, Wallace MR, Detection of varicella-zoster virus DNA in air samples from hospital rooms, 169 J Infect Dis. 91 - 4 (1994).) After initial infection, VZV establishes lifelong latency in cranial nerve and dorsal root ganglia, and can reactivate years to decades later as herpes zoster (FHZ) or “shingles.” (Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ, Neurologic complications of the reactivation of varicella-zoster virus, 342 N Engl J Med. 635-645 (2000).) More than 90% of adults in the United States acquired the disease in childhood, while the majority of children and young adults have been vaccinated with the live virus vaccine. (Marin M, Guris D, Chaves SS, Schmid S, Seward JF, Prevention of varicella : recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm Rep. 2007; 56:1- 40.). [0008] Several studies have associated infection, the recurrence of prior infection, and/or the reactivation of latent infection with administration of S1 P receptor modulators or agonists to individuals. For example, studies have suggested Varicella Zoster Virus (VZV) reactivation can occur in patients being administered immunomodulating treatments (e.g. Ma et al. , “Disseminated zoster with paresis in a multiple sclerosis patient treated with dimethyl fumarate,” Neurol Neuroimmunol Neuroinflamm. 2016 Apr; 3(2): e203.). VZV is not only a painful condition, but is also dangerous and potentially fatal.

[0009] It has been observed infections in individuals undergoing immunomodulating treatments can be particularly severe. For example, VZV infection has caused the death of clinical trial participants while the participants were undergoing treatment involving an immunomodulating agent (e.g. Arvin at al., “Varicella-Zoster Virus Infections in Patients Treated With Fingolimod,” JAMA Neurol. Author manuscript; available in PMC 2017 Apr 13.). Accordingly, the possibility of infection, recurrence of prior infection, or reactivation of a latent infection can result in medical providers recommending against treatment, or in at- risk patients declining or delaying treatment, for certain diseases or disorders, including autoimmune disorders (e.g. multiple sclerosis).

[0010] Despite the existence of modern technology, many patients encounter barriers to effective healthcare that limit or delay the ability to receive adequate treatment. In certain circumstances, delay can impact prognosis or evolution of the progression of a disease, including autoimmune diseases. For example, where patients must be tested for certain indicia prior to receiving a medical intervention, for example risk of certain infection prior to receiving S1 P receptor modulator or agonist therapy, limited access to medical facilities can prolong the time before treatment can be administered, especially if the patient requires another medical intervention (e.g. a vaccine) before receiving the treatment needed.

[0011] Barriers to effective healthcare that limit or delay the ability to receive adequate treatment include the absence of healthcare facilities in rural areas, tribal reservations, or other locations distant from treatment centers, laboratories, clinicians, or specialists. [0012] Accordingly, there is a need to develop kits which lower or eliminate the barriers to effective healthcare and/or accelerate the ability of patients to receive medical interventions, including interventions that involve S1 P receptor modulators or agonists.

SUMMARY

[0013] The inventors of the present application have developed kits addressing these needs. Surprisingly, it has been found that by administering a S1 P receptor modulator or agonist, such as Fingolimod, using kits according to the present application, it is possible to accelerate treatment for patients having barriers to receiving effective or adequate medical treatment. These kits permit fast and efficient treatment while controlling, reducing, or eliminating possible adverse events, e.g. infection, recurrence of infection, or reactivation of latent infection, which may be associated with administration of such a compound.

[0014] The kits provided according to the present application are applicable for patients who are presently undergoing treatment for an inflammatory or autoimmune or disease or disorder, for example under treatment for multiple sclerosis, as well as patients who were never treated or were not diagnosed for an inflammatory or autoimmune or disease before taking a S1 P receptor modulator or agonist.

[0015] The kits according to the present application include a dosage regimen for a S1 P receptor modulator or agonist therapy, which enables administration of a therapeutic dosage range of the S1P receptor to be achieved with controlled or minimal side effects, which could otherwise have been possibly associated with S1 P receptor modulator therapy.

DETAILED DESCRIPTION

S1P RECEPTOR MODULATORS

[0016] The present application encompasses S1 P receptor modulators, agonists, and antagonists. In some embodiments, the S1 P receptor modulators, agonists, and antagonists are compounds as described in U.S. Patent 5,604,229, and U.S. Patent 8,324,283. [0017] In a preferred embodiment of the present application, the S1 P receptor modulator is Fingolimod. In the present application, Fingolimod may be referred to as by its lUPAC name, which is:

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1 ,3-diol.

[0018] In the present application, Fingolimod may also be referred to by its trade name, GILENYA. In the present application, Fingolimod may also be referred to by the designation FTY720.

[0019] In the present application, Fingolimod may also be referred to by chemical structure, shown below:

[0020] It will be understood by a person of ordinary skill in the art that such designations of Fingolimod are interchangeable, and each designation refers to the same compound.

[0021] Other preferred embodiments of the present application include pharmaceutically acceptable salts, prodrugs, or stereoisomers of Fingolimod.

AUTOIMMUNE DISEASES

[0022] The present application encompasses the use of S1 P receptor modulators, including Fingolimod, to treat autoimmune diseases or disorders. According to the present application, such autoimmune diseases and disorders preferably include chronic long-term diseases, e.g. multiple sclerosis (MS), for example relapsing remitting multiple sclerosis (RRMS) or primary progressive multiple sclerosis (PPMS). MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms). [0023] In a preferred embodiment of the present application, the dosing regimens and methods of treatment according to the present invention are particularly adapted for multiple sclerosis, e.g. RRMS.

KITS

[0024] As set forth above, certain treatments for autoimmune diseases like multiple sclerosis, including Fingolimod, can place patients at risk for developing infection. Accordingly, under some circumstances, it may be advisable to assess the risk of infection or identify a patient at risk of infection prior to beginning treatment with Fingolimod.

[0025] However, it may not always be practicable to assess a patient’s individual risk for developing an infection based on certain barriers to effective healthcare, especially when the assessment involves taking samples from a patient and sending the samples to a laboratory for testing. Such barriers may delay the results of a test or assay intended to diagnose risk, thus delaying treatment of an underlying condition such as multiple sclerosis.

[0026] In some embodiments of the present application, the infection is caused by a bacteria, fungus, or virus. In some embodiments of the application, the infection is caused by a bacteria or virus selected from the group consisting of varicella zoster virus, adenovirus, bacillus anthracis (anthrax), vibrio cholerae (cholera), corynebacterium diphtheriae (diphtheria), hepatitis A, hepatitis B, haemophilus influenzae type b, human papillomavirus, seasonal influenza, japanese encephalitis, measles, Neisseria meningitidis (meningococcal), mumps rubulavirus (mumps), bordetella pertussis (whooping cough), pneumococcal, poliovirus (polio), rabies, rotavirus, rubella, variola major and minor (smallpox), Clostridium tetani (tetanus), mycobacterium tuberculosis (tuberculosis), salmonella enterica (typhoid fever), or yellow fever.

[0027] Accordingly, in some embodiments of the present application, a kit includes a first agent which includes a test for determining a patient’s risk. In some embodiments of the present application, the test includes testing a blood sample of the patient for the presence of antibodies to a pathogen causing the infection. In some embodiments, the test includes a serologic IgA, IgG, IgM, IgE, and/or IgD test. In some embodiments, the test includes a Radioimmunoassay (RIA). In some embodiments, the test includes an enzyme immunoassay (EIA). In some embodiments, the test includes a fluorescent immunoassay (FIA) In some embodiments, the test includes a chemiluminescent immunoassay (CLIA). In some embodiments, the CLIA assay includes an alkaline phosphate, galactosidase, glucose oxidase, glucose-6-phosphate dehydrogenase, b-N-acetylglucosaminidase, peroxidase, invertase, and/or xanthine oxidase label. In some embodiments, identifying a patient at risk for contracting an infection includes screening for pathogen-specific CD4 and/or CD8 cells. In some embodiments, the pathogen is varicella zoster virus. In some embodiments, identifying a patient at risk for contracting an infection includes a polymerase chain reaction (PCR) assay. In some embodiments, the PCR assay screens for DNA or RNA associated with a pathogen.

[0028] In some circumstances, certain antibodies (e.g. immunoglobins) are also present in saliva. Therefore, in some embodiments, identifying a patient at risk for contracting an infection includes testing saliva of a patient using one of the aforementioned techniques. In some embodiments, saliva may be obtained using a buccal swab or by spitting. In some embodiments, saliva may be analyzed using one of the aforementioned techniques, including Radioimmunoassay (RIA), enzyme immunoassay (EIA), fluorescent immunoassay (FIA), and/or chemiluminescent immunoassay (CLIA).

[0029] In an embodiment of the present application, the kit includes a CLIA directed to antibodies associated with a specific infection. In some embodiments, the infection is varicella zoster virus. In some embodiments, the presence of antibodies to varicella zoster virus in a patient’s blood indicates the patient is at a lower risk of varicella zoster virus infection. In an embodiment of the present application, the kit includes a buccal swap or a vessel for collecting saliva from spitting. In some embodiments, saliva obtained from the buccal swab or the vessel is analyzed by an assay included in the kit, e.g. a Radioimmunoassay (RIA), enzyme immunoassay (EIA), fluorescent immunoassay (FIA), and/or chemiluminescent immunoassay (CLIA).

[0030] CLIA is capable of modulating an amount of light produced by the assay in the presence or absence of a specific antibody or antigen. In particular, the CLIA assay emits photons when in the presence of the specific target. Thus, the CLIA assay is highly sensitive, develops quickly, and is easy to read by a physician. Accordingly, care providers in remote areas can utilize CLIA, or other tests according to the present application, to rapidly assess the risk of infection or identify a patient at risk of infection prior to beginning treatment with Fingolimod.

[0031] In some embodiments of the present application, the kit includes a second agent. In some embodiments, the second agent is a vaccine against an infection for which the patient is identified as having some risk to contract. However, because the vaccines of the present application can rapidly induce an immune response in a subject, it would not necessarily be required to first assess a patient’s individual risk before administering a vaccine.

[0032] In some embodiments of the present application, the vaccine is a recombinant vaccine. In some embodiments, the vaccine is a live attenuated vaccine. In some embodiments, the vaccine is an inactivated vaccine. In some embodiments, the vaccine is a subunit vaccine, In some embodiments, the vaccine is a polysaccharide vaccine. In some embodiments, the vaccine is a conjugate vaccine. In some embodiments, the vaccine is a toxoid vaccine. In some embodiments, the vaccine is a nucleic acid vaccine.

[0033] In some embodiments, the vaccine is a vaccine against an infection is caused by a bacteria, fungus, or virus. In some embodiments of the application, the vaccine is against a bacteria or virus selected from the group consisting of varicella zoster virus, adenovirus, bacillus anthracis (anthrax), vibrio cholerae (cholera), corynebacterium diphtheriae (diphtheria), hepatitis A, hepatitis B, haemophilus influenzae type b, human papillomavirus, seasonal influenza, japanese encephalitis, measles, Neisseria meningitidis (meningococcal), mumps rubulavirus (mumps), bordetella pertussis (whooping cough), pneumococcal, poliovirus (polio), rabies, rotavirus, rubella, variola major and minor (smallpox), Clostridium tetani (tetanus), mycobacterium tuberculosis (tuberculosis), salmonella enterica (typhoid fever), or yellow fever.

[0034] In a preferred embodiment of the present application, the vaccine comprises a varicella zoster virus gE antigen. In another preferred embodiment, the vaccine comprises a truncated varicella zoster virus gE antigen. In another preferred embodiment, the vaccine comprises a truncated varicella zoster virus gE antigen, in which the antigen is a C-terminal truncate. In another embodiment, the vaccine comprises a live-attenuated varicella zoster antigen.

[0035] In some embodiments of the present application, the vaccine comprises an adjuvant system. In some embodiments, the adjuvant system includes aluminum, aluminum salts, virosomes, squalene, MF59, vitamin E, ISA51 , Lipid A, MPL, 3D-MPL, LPS, RC-529, GLA, E6020, ONO-4007, aminoalkyl glucosamine-4- phosphates, CRX-527, CRX-547, CRX-601 , GSK1795091 , SLA, PHAD, 3D-PHAD, 3D-(6-acyl)-PHAD, OM-294, OM-174, OK-432, IL-1 , IL-2, IL-12, CpG 7909, Freund’s adjuvant, Quil-A, QS-21 , QS-7, compounds obtained or isolated from the bark of Quillaja, or combinations thereof. In a preferred embodiment, the adjuvant system of the present application includes MPL and QS-21. In another preferred embodiment, the adjuvant system of the present application includes MPL, QS-21 , and CpG7909.

[0036] In some embodiments of the present application, the adjuvant system includes a liposome. In some embodiments, the liposome includes amphiphilic lipids. In some embodiments, the liposome includes phospholipids. In some embodiments, the adjuvant system contains an oil in water emulsion. In some embodiments of the present application, the adjuvant system includes a salt of the adjuvant.

[0037] In some embodiments of the present application the vaccine is administered as a single dose. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 7 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 7 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 7 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 7 days.

[0038] In some embodiments of the present application, the kit comprises one or more doses of Fingolimod. In some embodiments, the kit comprises a plurality of doses of Fingolimod. In some embodiments, the plurality of doses includes a loading or titration or loading regimen as described herein below. In some embodiments, the plurality of doses includes one or more 0.5 mg doses of Fingolimod.

[0039] Accordingly, the kits of the present application permit rapid assessment of risk (if needed), vaccination against said risk, thus accelerating a course of treatment of an S1 P receptor modulator or agonist, such as Fingolimod. For example, a provider having a kit of the present application could assess whether a patient having multiple sclerosis (e.g. RRMS) is at risk of contracting an infection in less than a day, and, if necessary, administer the appropriate vaccination the same day. As discussed below, because the vaccines of the present application provide superior efficacy, it is possible to start the patient on Fingolimod in approximately 7, 14, 21 , 28, or 30 days, rather than the much longer time period it currently would take to do so. DOSAGE REGIMENS AND METHODS OF TREATMENT

[0040] In a preferred embodiment of the present application, the dosing regimens and methods of treatment according to the present invention are particularly adapted for multiple sclerosis, e.g. RRMS.

[0041] In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.5 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 1 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.1 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.2 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.25 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.3 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.4 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.6 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.7 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.75 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.8 mg per day taken once daily. In one embodiment of the present application, Fingolimod is administered at a daily maintenance dosage of 0.9 mg per day taken once daily.

[0042] In some embodiments of the present application, before the maintenance dosage, Fingolimod administration is initiated via a plurality of titration doses in a titration regimen. In some embodiments, the titration regimen includes a stepwise increase in the dose of Fingolimod. In some embodiments, the dose of Fingolimod on any given day is ±40% the combined dose of the previous two days (except for Day 1 , as no dose would have been given prior to Day 1 ). In some embodiments, the dose of Fingolimod on any given day is ±30% the combined dose of the previous two days (except for Day 1, as no dose would have been given prior to Day 1 ). In some embodiments, the dose of Fingolimod on any given day is ±50% the combined dose of the previous two days (except for Day 1 , as no dose would have been given prior to Day 1 ). In some embodiments, the dose of Fingolimod on any given day is ±20% the combined dose of the previous two days (except for Day 1 , as no dose would have been given prior to Day 1). In some embodiments, the dose of Fingolimod on any given day is ±10% the combined dose of the previous two days (except for Day 1, as no dose would have been given prior to Day 1).

[0043] In some embodiments, the titration regimen includes 1 day. In some embodiments, the titration regimen includes 2 days. In some embodiments, the titration regimen includes 3 days. In some embodiments, the titration regimen includes 4 days. In some embodiments, the titration regimen includes 5 days. In some embodiments, the titration regimen includes 6 days. In some embodiments, the titration regimen includes 7 days. In some embodiments, the titration regimen includes 8 days. In some embodiments, the titration regimen includes 9 days. In some embodiments, the titration regimen includes 10 days. In some embodiments, the titration regimen includes 11 days. In some embodiments, the titration regimen includes 12 days. In some embodiments, the titration regimen includes 13 days. In some embodiments, the titration regimen includes 14 days.

[0044] In some embodiments, the titration regimen is as follows: on Day 1 , the titration dose is 0.1 mg taken once; on Day 2, the titration dose is 0.1 mg taken once; on Day 3, the titration dose is 0.1 mg taken twice for a total of 0.2mg; on Day 4, the titration dose is 0.1 mg taken three times for a total of 0.3mg; on Day 5, the titration dose is 0.1 mg taken five times for a total of 0.4mg. In some embodiments of the present application, if one titration dose is missed for more than 24 hours, the plurality of titration doses are restarted with Day 1 of the titration regimen.

[0045] In some embodiments, the titration regimen is as follows: on Day 1 , the titration dose is 0.1 mg taken once; on Day 2, the titration dose is 0.1 mg taken once; on Day 3, the titration dose is 0.1 mg taken twice for a total of 0.2mg; on Day 4, the titration dose is 0.1 mg taken three times for a total of 0.3mg. In some embodiments of the present application, if one titration dose is missed for more than 24 hours, the plurality of titration doses are restarted with Day 1 of the titration regimen.

[0046] In some embodiments of the present application, before the maintenance dosage, Fingolimod administration is initiated via a plurality of loading doses in a loading regimen. In some embodiments, the loading regimen includes a stepwise increase in the dose of Fingolimod. In some embodiments, the dose of Fingolimod on any given day is ±40% the combined dose of the previous two days (except for Day 1 , as no dose would have been given prior to Day 1 ). In some embodiments, the dose of Fingolimod on any given day is ±30% the combined dose of the previous two days (except for Day 1, as no dose would have been given prior to Day 1 ). In some embodiments, the dose of Fingolimod on any given day is ±50% the combined dose of the previous two days (except for Day 1 , as no dose would have been given prior to Day 1 ). In some embodiments, the dose of Fingolimod on any given day is ±20% the combined dose of the previous two days (except for Day 1 , as no dose would have been given prior to Day 1). In some embodiments, the dose of Fingolimod on any given day is ±10% the combined dose of the previous two days (except for Day 1, as no dose would have been given prior to Day 1).

[0047] In some embodiments, the loading regimen includes 1 day. In some embodiments, the loading regimen includes 2 days. In some embodiments, the loading regimen includes 3 days. In some embodiments, the loading regimen includes 4 days. In some embodiments, the loading regimen includes 5 days. In some embodiments, the loading regimen includes 6 days. In some embodiments, the loading regimen includes 7 days. In some embodiments, the loading regimen includes 8 days. In some embodiments, the loading regimen includes 9 days. In some embodiments, the loading regimen includes 10 days. In some embodiments, the loading regimen includes 11 days. In some embodiments, the loading regimen includes 12 days. In some embodiments, the loading regimen includes 13 days. In some embodiments, the loading regimen includes 14 days.

[0048] In some embodiments, a titration regimen as described herein is followed by a loading regimen as described herein, which is then followed by a maintenance regimen as described herein. [0049] In some embodiments of the present application, before initiating the titration regimen, the method of treatment includes identifying a patient at risk for contracting an infection. In some embodiments of the application, the infection is caused by a bacteria, fungus, or virus. In some embodiments of the application, the infection is caused by a bacteria or virus selected from the group consisting of varicella zoster virus, adenovirus, bacillus anthracis (anthrax), vibrio cholerae (cholera), corynebacterium diphtheriae (diphtheria), hepatitis A, hepatitis B, haemophilus influenzae type b, human papillomavirus, seasonal influenza, japanese encephalitis, measles, Neisseria meningitidis (meningococcal), mumps rubulavirus (mumps), bordetella pertussis (whooping cough), pneumococcal, poliovirus (polio), rabies, rotavirus, rubella, variola major and minor (smallpox), Clostridium tetani (tetanus), mycobacterium tuberculosis (tuberculosis), salmonella enterica (typhoid fever), or yellow fever.

[0050] In some embodiments of the present application, identifying a patient at risk for contracting an infection includes testing a blood sample of the patient for the presence of antibodies to a pathogen causing the infection. In some embodiments, identifying a patient at risk for contracting an infection includes administering a serologic IgA, IgG, IgM, IgE, and/or IgD test. In some embodiments of the present application, identifying a patient at risk for contracting an infection includes a Radioimmunoassay (RIA). In some embodiments of the present application, identifying a patient at risk for contracting an infection includes an enzyme immunoassay (EIA). In some embodiments of the present application, identifying a patient at risk for contracting an infection includes a fluorescent immunoassay (FIA). In some embodiments of the present application, identifying a patient at risk for contracting an infection includes a chemiluminescent immunoassay (CLIA). In some embodiments, the CLIA assay includes an alkaline phosphate, galactosidase, glucose oxidase, glucose-6-phosphate dehydrogenase, b-N-acetylglucosaminidase, peroxidase, invertase, and/or xanthine oxidase label. In some embodiments, identifying a patient at risk for contracting an infection includes a polymerase chain reaction (PCR) assay. In some embodiments, the PCR assay screens for DNA or RNA associated with a pathogen.

[0051] In some circumstances, certain antibodies (e.g. immunoglobins) are also present in saliva. Therefore, in some embodiments, identifying a patient at risk for contracting an infection includes testing saliva of a patient using one of the aforementioned techniques. In some embodiments, saliva may be obtained using a buccal swab or by spitting. In some embodiments, saliva may be analyzed using one of the aforementioned techniques, including Radioimmunoassay (RIA), enzyme immunoassay (EIA), fluorescent immunoassay (FIA), and/or chemiluminescent immunoassay (CLIA).

[0052] In some embodiments of the present application, if a patient is identified as a patient at risk for an infection, the method of treatment includes vaccinating the at-risk patient to prevent the infection from occurring. In some embodiments, the vaccine is a recombinant vaccine. In some embodiments, the vaccine is a live attenuated vaccine. In some embodiments, the vaccine is an inactivated vaccine. In some embodiments, the vaccine is a subunit vaccine, In some embodiments, the vaccine is a polysaccharide vaccine. In some embodiments, the vaccine is a conjugate vaccine. In some embodiments, the vaccine is a toxoid vaccine. In some embodiments, the vaccine is a nucleic acid vaccine.

[0053] In some embodiments, the vaccine is a vaccine against an infection is caused by a bacteria, fungus, or virus. In some embodiments of the application, the vaccine is against a bacteria or virus selected from the group consisting of varicella zoster virus, adenovirus, bacillus anthracis (anthrax), vibrio cholerae (cholera), corynebacterium diphtheriae (diphtheria), hepatitis A, hepatitis B, haemophilus influenzae type b, human papillomavirus, seasonal influenza, japanese encephalitis, measles, Neisseria meningitidis (meningococcal), mumps rubulavirus (mumps), bordetella pertussis (whooping cough), pneumococcal, poliovirus (polio), rabies, rotavirus, rubella, variola major and minor (smallpox), Clostridium tetani (tetanus), mycobacterium tuberculosis (tuberculosis), salmonella enterica (typhoid fever), or yellow fever.

[0054] In a preferred embodiment of the present application, the vaccine comprises a varicella zoster virus gE antigen. In another preferred embodiment, the vaccine comprises a truncated varicella zoster virus gE antigen. In another preferred embodiment, the vaccine comprises a truncated varicella zoster virus gE antigen, in which the antigen is a C-terminal truncate. In another embodiment, the vaccine comprises a live-attenuated varicella zoster antigen. [0055] In some embodiments of the present application, the vaccine comprises an adjuvant system. In some embodiments, the adjuvant system includes aluminum, aluminum salts, virosomes, squalene, MF59, vitamin E, ISA51 , Lipid A, MPL, 3D-MPL, LPS, RC-529, GLA, E6020, ONO-4007, aminoalkyl glucosamine-4- phosphates, CRX-527, CRX-547, CRX-601 , GSK1795091 , SLA, PHAD, 3D-PHAD, 3D-(6-acyl)-PHAD, OM-294, OM-174, OK-432, IL-1 , IL-2, IL-12, CpG 7909, Freund’s adjuvant, Quil-A, QS-21 , QS-7, compounds obtained or isolated from the bark of Quillaja, or combinations thereof. In a preferred embodiment, the adjuvant system of the present application includes MPL and QS-21. In another preferred embodiment, the adjuvant system of the present application includes MPL, QS-21 , and CpG7909.

[0056] In some embodiments of the present application, the adjuvant system includes a liposome. In some embodiments, the liposome includes amphiphilic lipids. In some embodiments, the liposome includes phospholipids. In some embodiments, the adjuvant system contains an oil in water emulsion. In some embodiments of the present application, the adjuvant system includes a salt of the adjuvant.

[0057] In some embodiments of the present application the vaccine is administered as a single dose. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 30 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 28 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 21 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 14 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 90% in human adults within 7 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 95% in human adults within 7 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 98% in human adults within 7 days. In some embodiments, the single dose of the vaccine exhibits an efficacy of at least 99% within 7 days.

[0058] According to embodiments of the present application, a patient receiving a treatment regimen as described herein may therefore accelerate the start of the initial dosing regimen of Fingolimod as compared to the current state of the art.

[0059] Due to the rapid dose-response of the vaccines described in the present application, in some embodiments of the present application, there is no need to screen the patient for risk of contracting an infection before being vaccinated against the infection in anticipation of administration of Fingolimod. Due to the relatively high risk of infection, recurrence of infection, or reactivation of a latent infection in a patient undergoing treatment with an S1 P modulator, e.g. Fingolimod, it is desirable to mitigate the risk of infection in the patient by vaccinating against infection before starting Fingolimod. According to certain embodiments described herein, the patient may receive a vaccine against the infection and still commence treatment with Fingolimod within 30, 28, 21 , 14, or 7 days, unlike the current state of the art. Typically, screening a patient for risk of contracting an infection can take from several days to a week. Because the patient may commence Fingolimod after receiving a vaccination very quickly according to embodiments of the present application, in some instances it is is not necessary to screen the patient for risk of contracting an infection before administering the vaccine. In this way, the patient may accelerate the start of the initial dosing regimen of Fingolimod and decrease their infection risk as compared to the current state of the art. [0060] In a preferred embodiment, the patient may receive a vaccine against varicella zoster virus without being screened to identify risk of contracting a VZV infection. Because the VZV vaccine of the present application is highly-effective at a single dose within a short period of time, the patient is able to commence a Fingolimod regimen relatively quickly as compared to other treatment regimes.

[0061] In another preferred embodiment of the present application, the patient is administered a test to screen for the risk of contracting an infection. Before the results of the test are obtained, the patient is vaccinated against the infection. When the results of the test are obtained, if the patient is immune to the infection, the patient may begin treatment with the S1 P receptor modulator or agonist, e.g. Fingolimod, immediately. If the patient is not immune to the infection, however, the patient begins treatment with the S1 P receptor modulator or agonist, e.g. Fingolimod, once the vaccine has taken effect, i.e. , the patient has become immune to the infection or has substantially reduced the risk of infection as a result of the vaccine.

CLINICAL TRIAL

[0062] Investigation of clinical benefit of a method of treatment of Fingolimod.

[0063] 20 patients with relapsing-remitting MS receive said a vaccination according to the present application against varicella zoster virus. Serological data from each patient is collected at 7, 14, 21 , 28, and 30 days. Administration of the compound within an initial titration regimen followed by a maintenance dose. The general clinical state of the patient is investigated weekly by physical and laboratory examination. Disease state and changes in disease progression are assessed every 2 months by radiological examination (MRI) and physical examination. Initially patients receive treatment for 2 to 6 months. Thereafter, they remain on treatment for as long as their disease does not progress, and the drug is satisfactorily tolerated.

[0064] Main variables for evaluation: Safety (adverse events), standard serum biochemistry and hematology, magnetic resonance imaging (MRI).

Claims

1. A kit for treating relapsing remitting multiple sclerosis in a patient in need thereof comprising: a test for identifying a patient at risk of contracting infection; a vaccination for vaccinating the patient at risk of contracting the infection; and a dose of Fingolimod or a pharmaceutically acceptable salt thereof.

2. The kit according to claim 1 , wherein the test is a blood sample test of the patient adapted to determine the presence of antibodies to a pathogen causing the infection.

3. The kit according to claim 1 , wherein the test includes serologic screening of one or more of IgA, IgE, IgG, and IgM.

4. The kit according to claim 1 , wherein the test includes a saliva test.

5. The kit according to claim 1 , wherein the test is an immunoassay selected from the group consisting of radioimmunoassay, enzyme immunoassay, fluorescent immunoassay, and chemiluminescent immunoassay.

6. The kit according to claim 3, wherein the infection is caused by varicella zoster virus.

7. The kit according to claim 1 , wherein the vaccine comprises a recombinant antigen.

8. The kit according to claim 7, wherein the antigen is a recombinant antigen derived from a varicella zoster virus glycoprotein.

9. The kit according to claim 8, wherein the antigen is VZV gE.

10. The kit according to claim 9, wherein the varicella zoster virus gE antigen is a truncate.

11. The kit of claim 9, wherein the varicella zoster virus gE antigen is a C-terminal truncate.

12. The kit according to claim 1 , wherein the vaccine comprises an adjuvant selected from the group consisting of aluminum, aluminum salts, virosomes, squalene, MF59, vitamin E, ISA51 , Lipid A, MPL, 3D-MPL, LPS, RC-529, GLA, E6020, ONO-4007, aminoalkyl glucosamine-4-phosphates, CRX-527, CRX-547, CRX-601 , GSK1795091 , SLA, PHAD, 3D-PHAD, 3D-(6-acyl)-PHAD, OM-294, OM- 174, OK-432, IL-1, IL-2, IL-12, Freund’s adjuvant, Quil-A, QS-21 , QS-7, and compounds derived from the bark of Quillaja.

13. The kit according to claim 1, wherein the vaccine comprises a single dose of the vaccine, wherein the single dose exhibits an efficacy of at least 95% in human adults over 50 years of age within 21 days.

14. The kit according to claim 1 , wherein the vaccine comprises two doses of the vaccine.

15. A kit for treating relapsing remitting multiple sclerosis in a patient in need thereof, comprising: a vaccination for vaccinating the patient against an infection; and a dose of Fingolimod or a pharmaceutically acceptable salt thereof to said patient at a daily dosage, wherein the patient is not screened for risk of the infection before vaccinating the patent against the infection.

16. The kit of claim 15, wherein the infection is caused by varicella zoster virus.

17. The kit of claim 16, wherein vaccine comprises a recombinant varicella zoster virus antigen.

18. The kit of claim 17, wherein the varicella zoster virus antigen is a VZV gE C- terminal truncate.

19. The kit of claim 18, wherein the vaccine further comprises an adjuvant selected from the group consisting of aluminum, aluminum salts, virosomes, squalene, MF59, vitamin E, ISA51 , Lipid A, MPL, 3D-MPL, LPS, RC-529, GLA, E6020, ONO-4007, aminoalkyl glucosamine-4-phosphates, CRX-527, CRX-547, CRX-601 , GSK1795091 , SLA, PHAD, 3D-PHAD, 3D-(6-acyl)-PHAD, OM-294, OM- 174, OK-432, IL-1, IL-2, IL-12, Freund’s adjuvant, Quil-A, QS-21 , QS-7, and compounds obtained or isolated from the bark of Quillaja.

20. The kit of claim 19, wherein the vaccine comprises a single dose of the vaccine, wherein the single dose exhibits an efficacy of at least 95% in human adults over 50 years of age within 21 days.