TW200831122A - Treatment of multiple sclerosis (MS) - Google Patents

Abstract

A method for treatment of multiple sclerosis (MS) with Campath-1H with significant efficacy and a favourable safety profile is described, which offers an acceptable benefit/risk ratio. Especially described is the use of Campath-1H (alemtuzumab) for the production of a medlcament for the treatment of multiple sclerosis (MS), comprising a first treatment cycle followed by at least one further treatment cycle of Campath-1H (alemtuzumab), in which each treatment cycle comprises 1-5 daily doses which are applied on consecutive days, wherein the daily dose is > 0 and ≤12 mg, and wherein each treatment cycle is separated from the next cycle by at least 1 - 24 months. Also described are treatment regimens comprising the administration of less than 12 mg/day of Campath-1H for a period of 1-5 consecutive days.

Description

200831122 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a method for treating a multiple sclerosis (MS) with significant efficacy and good safety characteristics using Campas "H", which provides an acceptable benefit /risk ratio. The present invention also relates to the use of Campas-1H for the manufacture of a medicament for the treatment of multiple sclerosis (MS). [Prior Art] The sclerosis of the central nervous system of multiple sclerosis (MS) Demyelinating diseases, as many as 2.5 million people worldwide suffer from the disease. Little is known about the pathogenesis of MS, but it is believed to be between polygenic genetic susceptibility and unknown environmental factors. The interaction is caused by a female prevalence rate that is about twice that of men. Worldwide, the prevalence is geographically different and the prevalence among different ethnic groups varies in the same country. Countries far from the equator (eg Scotland and Scandinavia) The highest prevalence of Caucasians in Navia). The highest incidence is in the third and fourth decade; the new diagnosis is extremely rare in patients over 60 years old [National Multiple S Clerosis Society, General Information, Just the Facts: 2000-2001. National Multiple Sclerosis Society; 2001·] o Campas-1H (allezumab) is a recombinant DNA-derived humanized monoclonal antibody, Directly targeting 21-28 kD cell surface prion protein CD52. CD52 is a high-abundance molecule (about 5 X 105 antibody binding site) on at least 95% of all human peripheral blood lymphocytes and monocytes/macrophages. /cell) [Hale G. et al., The CAMPATH-1 antigen (CD52). Tissue Antigens 1990; 35:1 18-127] 〇124300.doc 200831122 Campas-1H is disclosed in U.S. Patent No. 5,846,534, which is incorporated herein by reference. A humanized antibody that binds efficiently to the antigen CD52, and a method of treating a human patient having a malignant lymphoma using the same. It discloses a procedure for preparing and testing the antibody. Campas-1H (Alai Group) Monoclonal antibody, Campath® or MabCampath®) has been approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and patients who have failed fludarabine therapy. Used to treat CLL Ming, Campas therapy begins with a 2 hour daily dose of 3 mg intravenously. When the patient is tolerated with a 3 mg dose of Campas, the dose is increased to 1 mg and continues to be tolerated. After the patient is tolerated with a 10 mg dose, a 30 mg/day maintenance dose of Campas is administered three times a week for 12 weeks (eg, Monday, Wednesday, and Friday) (see the Campath® Drug Handbook). Clinical studies have shown that Campas-1H antibodies are also active in a variety of other diseases, including graft-versus-host disease, organ transplant rejection, rheumatoid arthritis and other autoimmune diseases, and non-Hodgkin's ( Non-Hodgkin's) Lymphoma and leukemia [Hale G? Waldmann H. From laboratory to clinic: The story of Campath-1H in antibodies in the clinic. In: George AJT, Ureli C? ed. Methods in Molecular Medicine. Diagnostic and Therapeutic Antibodies: NJ: Humana Press; 2000;40:319-323] °

Hale and Waldmann first revealed the use of Campas _ 1H in multiple sclerosis. In U.S. Patent No. 6,120,766, Hale and Waldmann claim a method for treating multiple sclerosis in a human patient, 124300.doc 200831122, which comprises administering an effective amount of Campas_1H and an effective amount of a steroid (eg, Hydrocortisone ^ (methylprednis 〇 1〇ne). In this patent, it describes a 43-year-old woman with chronic progressive Ms who have been intravenously injected with a high dose. Prednisolone (second treatment: 5 mg/day, 5 days), but limited efficacy. The patient received 10 doses of Campas-1H within 12 days (2 mg/day for 5) Days, withdrawal for 2 days, then 1 mg / 曰 for 5 days. It is reported that fever and headache are adverse events during the first dose of 2 mg and 1 mg. Apply Campas _1H one to two After a month, the patient's Kurtzke nerve status improved and the improvement lasted for 18 months after treatment. Since then, Campas-1H has been used in primary MS and secondary progressive MS (respectively Various clinical studies in patients with PPMS and SPMS). For example, '1994 T. Mo Reau et al. reported that six SPMS patients and ppMS patients were treated with Campas ιη at 12 mg/day for 1 day. (Lancet (1994), 344: 298-301). 1996 T' Moreau Etc. Elected to treat 12 SPMS patients and one PPMS patient with Campas 1H at a dose of 2 mg/曰5 days, then 10 mg/day for 5 days, or 12 mg/曰 for 10 days, or 2 使用Mg/day 5 days (Brain (1996), 119: 225-237). It reports that serum cytokine release and transient symptoms worsen with the first infusion of Campas and induced lymphopenia and previous invasive CNS Transmission changes in the pathway are associated. In 1999, Coles et al reported that 29 SPMS patients were treated with a dose of 20 mg/day for 5 days (Ann. Neurol. (1999), 46: 296-304). Doc 200831122 A brief reversal of previous or current symptoms during the first Campas-1 dose. About half of the patients underwent progressive disability and enhanced brain atrophy, which was attributed to axonal degeneration as determined by MRI spectroscopy. , Coles et al. report on the long-term outcomes of 27 patients reported in previous studies Trace observation (Lancet (1999), 354: 1691-95). One-third of patients develop antibodies against the snoring hormone receptor and Carbimazole-sensitive autoimmune hyperthyroidism (Gravesf disease) 〇 In 2003, Coles et al reported a recurrence rate in an average of 7 years of follow-up observations of 36 SPMS patients who received Campas-1H since 1991. Keep it low but its disability continues to progress. In addition, one third (1/3) of patients develop Griffith's disease (Neurology 60 March 2003 (Suppl. 1)). It also reported treatment of 22 patients with relapsing-remitting MS (RRMS). Subsequent reports from the 22 RRMS patients confirmed that they received a dose of 20 mg/曰 for 5 days and received a selective retreatment of 20 mg/day for 3 days after 12-18 months (Clinical Neurology and Neurosurgery (2004), 106:270-274). The main adverse event was Graves' disease, which occurred within 5-21 months of the first treatment (14 patients) and within 2 years after the second cycle (one patient), with a total of 15 out of 57 patients. (27%) (a patient with Glyphs' disease before receiving Campas-1H). MS Technology and Science Conference in Toronto, 2004 (Art and

Science of MS Meeting) Captain 'Donne 11 reports a comparison of two dose levels of Campas-1H and interferon beta-la in an active RRMS patient in an ongoing trial (Rebif®, Ares-Serono ). In the test 124300.doc 200831122 (CAMMS223), the dose of 12 dg / day (low dose) or the dose of mg / day (high dose is Kansas) 5 days. Interferon group patients such as products The label (Off _ _ said that three times a week subcutaneous injection. CAMMS223 experimental period, the results were announced by the company and his AG AG__ September 16, 2005. These results are from a predetermined performance and safety mid-term As a result of the analysis, the analysis was administered at a low (123⁄4 g/曰) or high (24 mg/曰) dose in 4 years of intravenous treatment for all patients in the planned three-year trial. Campas _ 1H for 5 days' treatment of patients three times a week as described in their product label + Interferon ia. In 12 months, patients in the Campas 1H group received 12 or 24 mg / day The dose was up to 3 days. Patients who used Campas at high and low doses had a reduced risk of recurrence of at least 75% after at least one year of follow-up compared with patients treated with interferon p_la. In addition, compared with patients in the Rebif8 group Patients in the Pas group have a reduced risk of clinically significant disability of at least 6% However, two cases of severe idiopathic thrombocytopenic purpura (ITp) were reported (two in the high-dose group and one in the low-dose group). During the ECTRIMS in 2005, Fox et al also reported a failure in the treatment of licensed IFN-β. High-dose Campas study of 45 active patients. Campas was given 5 days at 24 mg/day and 3 mg at 24 mg/day after one year. A serious drug-related adverse event occurred. Neutrophilic leukopenia and pneumonia) and abnormal thyroid values found in several patients. In summary, the administration of Campas-1H to MS patients has been shown to be effective in treating disease, but this administration is accompanied by adverse events. These adverse events may include infectious and autoimmune complications. Therefore, there is still a need to have significant efficacy in the patient population 124300.doc • 10 - 200831122 (ie reduce the risk of recurrence and/or reduce clinically significant disability). The risk of ordering) has the acceptable safety characteristics of the invention. [Invention] The invention relates to a method for treating multiple sclerosis (MS) in patients with 瘠* and +^縻. One cycle is in μ, ττ is the person Pas_1Η, and then another cycle to Campas-1Η, pots, sputum, and each treatment cycle includes 1-5 doses for several days. Wherein the dose per dose> and < hair brother and wherein each treatment cycle is at least 1-24 months apart from the next cycle. In some embodiments, the patient is retreated at a fixed time, $ U疋 time, For example for the first time

6, 12, 18 or 24 months after treatment. In the case of the straight object A n in other real targets, the patient was re-treated only when evidence of recurrent MS activity was observed. In one embodiment, retreatment is performed at the same dose and duration as the first treatment. In other embodiments, the retreatment is performed with a duration that is different for the first treatment, or a duration of the same amount. The present invention is also directed to a method for treating multiple sclerosis in which I am suffering from a dose of less than 12 mg/day of Campas 丨11. The invention also relates to the use of Campas_1H for the manufacture of a medicament for administration according to the methods described herein. The methods and uses of the present invention are useful in patients with relapsing MS and in patients with progressive MS. The above summary and the following embodiments are merely illustrative and illustrative and not restrictive. [Embodiment] The term "Kampas_1H" as used herein refers to the same list of antibodies (also known as alemtuzumab) disclosed in U.S. Patent No. 124300.doc 200831122 W46'534, and with Campa Human or humanized monoclonal antibodies of the same CDR sequence. In one aspect, the invention relates to the use of Campas in the manufacture of a medicament for the treatment of a relapsing MS patient, characterized in that the Campas η is administered at a dose of less than 12 mg/day for 5 consecutive days. In another aspect, the invention relates to a method for treating a relapsing side which comprises administering Campas-1Η at a dose of less than 12 mg/day for 5 consecutive days. In another aspect, the present invention relates to a method for treating a patient with ms: a method comprising: applying a Campa calculation at a dose of less than 12 mg/曰 for 5 days; and using the dose at a dose (mg/day) And/or duration (days), or less than the initial regimen treatment regimen to treat the patients. In the example, the second is read by Campas for 5 days. In another embodiment, with or; or two days, 9. , 8, 7, 6, 5, or 4 mg / day dose is applied in the Campasda 2 method. 'This invention is related to the species used to treat MS's square-1H Da: Γ to the most, back The dose of gram/曰 周期性 is periodically administered with Campa's interval 'each treatment cycle and pre-cycle (ie, given Campas-1H) for at least 1 month. Apply Campas_1H in a specific implementation. In the example, in the different embodiments, the daily dose of the treatment period in each cycle can be kept constant or the treatment period is 5 ancient "1 brother one cycle is mg/ Day, follow-up week... Day) The inventor also considered giving a gift in a treatment cycle by, for example, 1243〇〇.d〇c -12- 200831122 (for example, 8 mg for one day and i〇 mg for the next day) The third day is 1 2 home gram, etc.) or the decreasing dose of sputum. The number of consecutive days of treatment (i.e., administration) in each cycle is typically 1-5 days. In some embodiments, one cycle is 1-3 days. The number of days of administration in each cycle may remain the same or the number of days of administration will be different in different treatment cycles (eg, 3 days in the first cycle and 2 days in the post-period). Reducing the number of days per cycle may improve patient convenience/ Acceptability and reduced cost of treatment. In another aspect, the invention

......•小'1, ▼8 π on the use of the drug for the treatment of MS, including the periodic application of Campas-mu days at a daily dose of up to 12 mg / day, Each treatment cycle is at least 1 month apart from the pre-cycle (ie, given Campas-1H). In some embodiments for periodic administration, consecutive treatment cycles are separated by at least 3 or 6 months. The interval is at least (4) solid γ. In a particular embodiment, the number of consecutive treatment cycles is unlimited, such that: life-long treatment is performed. In still other embodiments, the number of treatment cycles is limited to 2-10 or 2-5 cycles. In the second part of the treatment, re-treatment is performed at a fixed time course, for example, after the first u treatment for 6, 12, 18 or 24 months. MS is in another aspect of the second, only in each patient. Retreatment is performed when evidence of recurrence/motility is observed (ie, the treatment cycle of sputum doses of sputum). In this article, broth (1) requires retreatment. “Therapeutic regimen means “based on clinical treatment available to physicians. The physician's professional judgment uses this method to determine evidence of recurrence of Ms activity. 4300.doc -13- 200831122 Current physicians can use a variety of techniques to diagnose recurrent MS activity, including (but not limited to) by clinical methods (recurrent or progression of neurological disability) or by magnetic resonance imaging (MRI) of the brain or spinal cord Practitioners should fully understand that disease activity detected by MRI can be indicated by a new brain or spinal cord injury or an increase in the volume of such lesions that appears on T1 (enhanced or unenhanced) or 12-weighted images. The diagnostic methods are constantly evolving, and other methods for detecting recurring MS activity (such as magnetization transfer rate or MR-spectroscopy) are expected in the future. The specific diagnostic method for detecting the recurrence of Ms activity is not limiting the present invention. In some embodiments, MRI is repeated at regular intervals after a treatment cycle to determine if any given patient needs re-treatment and re-treatment of the patient at the optimal time point. In general, re-treatment is performed prior to the sub-sex. It is expected that in the clinical context, it is expected that the "re-treatment as needed" strategy can potentially avoid patients by continuously suppressing ms. Unnecessary drug exposure of the herein disclosed treatment regimen of benefit / risk ratio is maximized. Retreatment of the embodiment comprises a 'may be administered for the acute relapse

曰 dose of Campas-1H for 1-5 days, bowel administration of up to 12 mg / day, each of which was observed only in each patient 124300.doc •14· 200831122 was only implemented when evidence of MS activity Retreatment. All methods and uses of the present invention are applicable to both relapsing and progressive multiple sclerosis (MS). It is currently expected that patients with relapsed MS will respond better than patients with progressive disease. The MS patient who can receive the treatment may be a patient who is initially treated with another drug or a patient who has not received previous MS therapy (ie, a patient who is not (drug) treated). In the methods and uses of the invention, Lisin-1H can be administered via any acceptable route including, but not limited to, parenteral administration (eg, intravenous, subcutaneous, intramuscular, intraperitoneal, menstrual) Nasal, transpulmonary). In certain embodiments, Campas-1H can be administered intravenously (Lv.) or used to make an intravenously administered agent. In the case of a premediCati〇n, it is possible to use any drug known to the skilled artisan to be effective for this purpose, such as steroids (before infusion, infusion/main or in/after the main). For example, methylprednisolone, aeetamin〇phen, and antihistamines (such as diphenhydramine) to control infusion-related side effects. In certain embodiments, only low doses of such drugs are used during the initial 丨3 days of administration in each treatment cycle. In other embodiments, the concomitant drug is not administered. The use of Campas_1H treatment according to the method of the invention and the use of Campas-1H according to the invention for the manufacture of medicaments may result in a low incidence of (serious) adverse events. It is therefore expected that the MS treatment regimen of the method of the invention will yield an acceptable benefit/risk ratio. In accordance with the present invention, Campas_1H is administered as a suitable pharmaceutical formulation containing suitable excipients known to those skilled in the art or used in the manufacture of 124300.doc -15-200831122 for administration . The current Campath® (MabCampath®) formulation represents an example of this suitable product (see the Campath® Drug Specification). In addition to the solution, Campas-1H can also be formulated as a freeze-dried product that is reconstituted immediately before use. 0 The formulation is preferably provided in a glass or plastic bag (mainly for intravenous injection) but can also be viewed as a route of administration. Other standard containers known to those skilled in the art (e.g., pre-filled syringes for subcutaneous administration or spray (aerosol) containers for nasal and transpulmonary use) are used. Thus, the advantages of the present invention are: • maximization of benefit/risk ratio and/or • minimization of drug exposure and/or • improved patient convenience/acceptability and/or • reduction in infusion-related side effects and/or • Reduced opportunistic infection rates and/or • reduction in thyroid abnormalities (including Gryffosis) and/or reduction in autoimmune blood complications (eg thrombocytopenia) and/or • other (severe) malnutrition Reduction of events and/or • Minimization of antibody formation against Campas-1H In certain embodiments of the invention, two initial fixed treatment cycles are between 1 and 24 months apart, after which only recurrence is observed. 8 The second treatment cycle or subsequent treatment cycle (ie, " re-treatment as needed.) Therefore, any symptomatic treatment (such as steroids) administered after acute recurrence may be performed or after Immediately start the third treatment cycle or the subsequent treatment cycle (ie no fixed interval (time period) during the subsequent treatment cycle). Or, only after 124300.doc -16 - 200831122 brother one (w times) treatment cycle has passed Re-treatment for relapsed MS activity is performed 3 to 24 months later. In one embodiment of the invention, Campas-1 is administered in a dose of 1 mg/twice for the first two consecutive days or The agent used to make the initial dose (month 0) is then subjected to a second fixed treatment cycle of 1 mg/day for two consecutive days at month 12. It is then based on re-treatment as needed. Subsequent retreatment is performed in a plurality of cycles of 103⁄4 g/day for two days. In another embodiment of the invention, Campas 丨 is administered initially with 12 mg/曰 of the agent for 5 consecutive days for 5 days. Manufacture of the first dose (month 0) of the agent' followed by a second fixed treatment period of 12 mg/曰 for 3 consecutive days at the 12th month. Then only based on the need for retreatment according to the need for another one or more 12 Subsequent retreatment is performed during a three-day period of residence/day administration. It is expected that such treatments and regimens will result in sustained consumption of lymphocytes and a proportional degree of clinical benefit, while providing safety superior to those previously used for this patient population. Sexuality The protocol was developed based on the pharmacokinetics and pharmacodynamics analysis of the Campas_1H in patients who were enrolled in the clinical trial of CAMMS223. Various pharmacokinetic and pharmacodynamic models were developed for the purpose of this analysis. Model selection is based on the principles of physiology and pharmacology and the principle of simplicity - if statistically proven to be effective, choose a simpler model rather than a more complex model. First, perform exploratory data analysis to examine the basic structure of concentration-time data. And identify any outliers. Second, develop various structural models without covariates (such as the two-compartment model). Once the basic structural model is determined, the covariate 124300.doc 200831122 is included in the model to see if it is improved. ^ — 1 degree. Once the most metabolic kinetic model is determined, the 炱^^ 1 ^ &> number is fixed and a pharmacodynamic model is formed. Only one type of model, the thinning type, has been shown to be a good model for biomarkers such as blood indices. Once the final pharmacokinetics/drug effect kinetics were determined, the control parameters were fixed and a deterministic simulation was performed to test the method pairs and lymphocyte counts in alternating dose history. Verify the following dosing regimen/use:

Re-treatment with 3 days / 1 1 administration at 24 mg for 5 days and then 24 mg per year; treatment with 12 mg for 3 days for re-treatment / administration for 1 day for 2 days for re-treatment / for 10 mg for 1 day Treatment/administration with 4 mg for 3 days for retreatment/6 mg for 1 day for retreatment/3 mg for 1 day for retreatment/1 oz for 1 day for retreatment/2 for 12 mg 5 days and then used every year; 3 · Apply for 10 days at 10 oz and then for each year; 4. Apply for 10 days at 10 oz and then use for each year; 5. Apply for 5 days at 4 mg and then use for each year; Apply 1 day and then use each year; 7 · Apply 5 days for 1 day and then use for each year; and 8 · Apply 1 mg for 1 day and then use 0 124300.doc -18- 200831122 for the sake of simplicity. Day x dose. Thus, for example, five doses of 12 mg can be numbered 5<12 mg, and a single mg dose can be numbered 1 X 10 mg or the like. The pharmacokinetic and pharmacodynamic models of drug effects show that Campas can consume lymphocytes very efficiently. A single dose of 5 mg reduced lymphocytes by about 50%, with the lowest point occurring after about 1 week of dosing. In addition, the model showed no increase in dose resulting in increased lymphocyte depletion, and lymphocytes were almost completely depleted in the 5 χΐ 2 mg treatment group. The specific results of this analysis are recognized as Campas that are expected to be delivered in a two-day cycle of 10 mg/day administration and 2 days (ie 20/20 mg regimen) re-treatment at 12 mg/day at 12 months. Treatment with 1H can result in sustained lymphocyte depletion that is only slightly lower than the higher dose. Given that the mechanism of action of Campas 1 is due to immunosuppression, it is expected that a small reduction in lymphopenia will only be associated with a similarly small decrease in potency. Therefore, it is expected that this 20/20 regimen will result in a slightly lower level of lymphocyte depletion compared to the previously studied protocol. It is expected that a lower Campas 丨Η dose delivered with less infusion can provoke less acute infusion reactions and limit the likelihood of adverse events typically associated with intravenous (i v ) injections. Considering the conventional immunosuppressive effect of Campas-1H, lowering the dosage can also reduce the risk of infectious complications. It is also expected to reduce the relative risk of autoimmune complications. The following examples demonstrate the feasibility of the invention and are not intended to limit the invention to the examples. Example 1 In an early stage of active treatment of recurrent relapsing-remitting multiple sclerosis 124300.doc •19- 200831122, an open randomized multicenter trial conducted by an open assessor was performed. The first treatment cycle for Campas-1H included 5 doses of 12 mg of the daily dose in the second month. The second (fixed) treatment cycle consisted of three doses of 12 mg of bismuth sputum administered in the 12th month. Thereafter, re-treatment was performed with 3 doses of 12 mg Campas_1H daily dose only when evidence of recurrent Ms activity was observed in each patient. Therefore, the third and subsequent cycles are administered only when the patient has evidence of recurrent MS activity, and recurrent MS activity is defined in this example as at least one documented clinical relapse or treatment with previous Campas 1Η There were at least 3 new MRI lesions (total) compared to the cis (ie, retreatment regimen as needed). The right meets these criteria and the patient can be retreated immediately. If the patient with Campas-1H receives a symptomatic recurrence within 2-8 weeks prior to the scheduled/planned alemtuzumab infusion, the infusion and steroids can be delayed until use. Two to eight weeks after the treatment of relapsed steroids. Steroid pretreatment is usually administered during the first three days of the Campas _1H infusion to avoid/minimize infusion-related side effects. The continuous treatment cycle should follow the same "re-treatment as needed" rules as described above. Patients can receive an intravenous injection of methylprednisolone (IV) over the first 3 days of each treatment cycle to alleviate any cell target release syndrome. Example 2 Treatment of MS patients as described above, except that the first treatment cycle of Campas _1H includes two daily doses of 1 mg in the 0th month and a second treatment cycle including 1 G mg twice in the first application. Daily dose. Thereafter, the patient was retreated with a daily dose of 2 gram of 124300.doc -20-200831122 Pas-1H only when evidence of relapsed MS activity as described in Example 1 was observed. Example 3 Ms patients were treated with the same treatment regime as described in Example 1 or 2, ', second and subsequent retreatments were re-treated as needed, provided that the previous Campas-1H treatment cycle (dose period) After at least 6 months. Example 4 Ms patients were treated with the same treatment regime as described in Example 3, however, evidence of recurrent MS activity was observed at any time after the first (previous) Campas-1H treatment cycle (dose period) and if Each patient was retreated with the patient who did not receive a symptomatic treatment for recurrence within 2-8 weeks prior to the planned Pass-1H cycle. If the patient has received steroids within 2-8 weeks prior to the planned Campas cycle, retreatment begins after the completion of steroid treatment 2 . ^Example 5 The MS was treated with two Campas_1H treatment cycles using the dosing regimen as described in Example 1 or 2. However, after the second cycle of the 12th month, the recurrence of disease activity was not treated and re-treatment was performed at 18 months intervals). .燎 (solid

All publications (including patents) cited in this specification are hereby incorporated by reference. Gu Bai U [Simple diagram of the diagram] Figure 1 shows an example of a simulated dosing regimen within 24 months. In the figure, a group of figures means the number of days X daily dose. For example, 5"2 mg means 12 mg per day for 4 hours in 5 days. One and the number is 124300.doc -21- 200831122 refers to the dose re-treated at 12 months. Figure 2 shows at 12 A line graph of the simulated dosing regimen for the month. Figure 3 shows a line graph of the selected dosing regimen from Figure 1. The data for the two 10 mg doses administered during the first cycle are covered by each other and cannot be mutually Identification 0 I24300.doc -22 -

Claims (1)

200831122 X. Patent application scope · 1β A medical combination for the treatment of multiple sclerosis (MS) in patients, including 1-5 doses of Campas _lH and another to one cycle of the first cycle The 1-5 doses of Campas ιη, wherein each dose is > and $12, and administered for several consecutive days, wherein each cycle is separated from the next cycle by at least 1. 24 months. 2. The pharmaceutical combination of claim 1, wherein the additional at least one cycle is applied 12 months after the first cycle. > The pharmaceutical combination of claim 1, wherein the additional at least one cycle is administered after detecting recurrent MS activity. A pharmaceutical combination according to claim 1, wherein the Campas is administered at a dose of 10 mg/day for two days. ..., 5 · The pharmaceutical combination of claim 1, wherein the first cycle of the 坆Pago #八T忑故帕斯-1H is administered for two days at a dose of 2 grams/day. 6. If the request item ^ is any of the other to the doctor's advice, and δ, where the dose of Campas-1H. Chips/, have the same duration and every 7th, as in any of claims 1-5, at least one, month #, -..., , and δ, where the period of Campas _m Has the same duration as each of the first cycles. 4 U of the daily dose 8 and 8 · If the request group ΐ / Φβ ^, 5 of the medical group, at least one other # s + λ where the period of Campas-m has the first 9 • A daily dose with a low cycle in the request. A pharmaceutical combination of any of 5, a straight MS. In this case, the patient has a recurrence of 124300.doc 200831122 1〇·1 item 4 of the medical combination, wherein after detecting the recurrent MS activity, the application is applied for two days at a dose of 103⁄4 g/day of Campas 111. The pharmaceutical combination is re-administered to the patient in another cycle. 1L. The pharmaceutical combination of claim 4, wherein the pharmaceutical combination is re-administered to the drug cycle at another cycle of two days of application of a dose of 1 gram per day for 12 months after the first cycle. patient. 12. The pharmaceutical combination of claim 5, wherein the pharmaceutical combination is re-administered to the drug cycle at another 12 days of application of a 12-kilogram/day dose of Campas_1H for 12 months after the first cycle. patient. 13. The pharmaceutical combination according to claim 5, wherein the pharmaceutical combination is re-administered to the patient after another three days of application of a dose of 123⁄4 g/day of Kampas_1H after detecting recurrent MS activity . 14. A pharmaceutical combination as claimed in claim 2 or 2 wherein each treatment cycle is at least 6 months apart from the next cycle. 15. The pharmaceutical combination of claim 1 or 2, wherein each treatment cycle is at least 12 months apart from the next cycle. 16. A combination of medicines of claim 2 or 2, wherein each treatment cycle is at least 18 months apart from the next cycle. 17. The pharmaceutical combination of claim 1 or 2 wherein each treatment cycle is at least 24 months apart from the next cycle. 18. A pharmaceutical combination for treating multiple sclerosis in a patient comprising administering a Campas-1H at a dose of less than 12 mg/stroke for a continuous period of 1.5 days. 19. The use of a Campas-1H for the manufacture of a medicament for the treatment of multiple sclerosis, which is administered at a dose of less than 12 mg/stroke for a period of iv_5 days, 124300.doc 200831122. Use of the human Pas 1H for the manufacture of a medicament for the treatment of multiple sclerosis (ms) comprising a first treatment cycle of Campas, followed by at least one additional treatment cycle, wherein each treatment cycle comprises 15 daily doses The administration is for several consecutive days, wherein the daily dose > 0 and 2 milligrams, and wherein each treatment cycle is at least 1 month apart from the next treatment cycle. 21. The use of claim 19 or 20, wherein the daily dose is between 4" and 〇mg. 22. The use of claim 20, wherein each treatment cycle is separated from the next cycle by at least 6 months. 23. The use of claim 20, wherein each treatment cycle is separated from the next cycle by at least 12 months. 24. For the purposes of claim 20, each treatment cycle is separated from the next cycle by at least 18 months. 25. The use of claim 20, wherein each treatment cycle is separated from the next cycle by at least 24 months. 26. The use of claim 20, wherein the number of consecutive days of treatment per cycle is 1-3 days. The use of any of claims 20 and 22 to 26, wherein the additional at least one treatment cycle is administered when a relapsed MS activity is found. 28. The use of a Campas-1H for the manufacture of a medicament for the treatment of multiple sclerosis (Ms) comprising two initial fixed treatment intervals of 1 to 24 months, followed by the discovery of recurrent MS activity A third or subsequent treatment cycle is performed at the time of sex. 124300.doc 200831122 29. The use of Campas-1H of claim 28, wherein the treatment cycle is only after the second treatment cycle has passed at least a third or subsequent treatment for 3-24 months. 124300.doc