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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• This invention relates to use of teriflunomide for treating Multiple Sclerosis (MS) and managing the risks associated with the use of teriflunomide.
• MS Multiple Sclerosis
• Teriflunomide is a novel oral disease-modifying therapy (DMT) in development for the treatment of relapsing-remitting multiple sclerosis (RMS).
• DMT oral disease-modifying therapy
• RMS multiple sclerosis
• Teriflunomide blocks de novo pyrimidine synthesis, which inhibits the replication and function of activated (but not resting) lymphocytes.
• This invention relates to a method for reducing annualized relapse rate (ARR) in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• ARR annualized relapse rate
• This invention also relates to a method for delaying disability progression in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Figure 1 shows the patient disposition through the TEMSO study.
• Figure 2 shows the time to first relapse and patients remained free of relapse in the three patient groups in the TEMSO study.
• Figure 3 shows the 12-week-confirmed disability progression of the three patient groups in the TEMSO study.
• Figure 4 shows the mean number of T1 -Gd-enhancing lesions (A) and proportion of patients free from T1 -Gd-enhancing lesions (B) of the three patient groups in the TEMSO study.
• Figure 5 shows the number of unique active lesions per scan of the three patient groups in the TEMSO study.
• Figure 6 shows the change from baseline in burden of disease over time of the three patient groups in the TEMSO study.
• Figure 7 shows mean change from baseline in the volume of T1 hypointense lesions of the three patient groups in the TEMSO study.
• “Clinically proven effective” means the efficacy of treatment has been proven by a Phase III clinical trial as statistically significant with an alpha level less than 0.05 or the clinical efficacy results are sufficient to meet approval standards of U.S. Food and Drug Administration.
• EDSS means the Kurtzke Expanded Disability Status Scale.
• One embodiment of the invention is related to a method for reducing annualized relapse rate by about 31 .5% in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the risk of disability progression in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the risk of disability progression by about 29.8% progression in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing burden of disease in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing burden of disease by about 67.4% in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the number of Gd-enhancing T1 lesions per scan in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of
• teriflunomide daily wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the number of Gd-enhancing T1 lesions per scan by about 80.4% in a patient having relapsing form of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for improving proportion of patients free from Gd-enhancing T1 lesions in patients having relapsing-forms of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for improving proportion of patients free from Gd-enhancing T1 lesions to about 64.1 % in patients having relapsing-forms of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the number of unique active lesions per scan in a patient having relapsing-forms of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of
• teriflunomide daily wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the number of unique active lesions per scan by about 69.4% in a patient having relapsing-forms of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the T1 hypointense lesion volume in a patient having relapsing-forms of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another embodiment of the invention is related to a method for reducing the T1 hypointense lesion volume by about 31 .3% in a patient having relapsing-forms of multiple sclerosis in need thereof, comprising administering to the patient 14 mg of teriflunomide daily, wherein the method is clinically proven effective.
• Another aspect of the invention is related to managing the risks associated with the use of teriflunomide for treating multiple sclerosis.
• Another embodiment of the invention is related to a method for managing the risk of elevation of liver enzyme to allow an effective and safe use of teriflunomide or a pharmaceutically acceptable salt thereof in the treatment of multiple sclerosis in a patient in need thereof comprising:
• transaminase and bilirubin levels are measured within six month prior to the treatment.
• the method can further comprise the following steps:
• liver enzymes during the treatment particularly to the patient who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia or jaundice and/or dark urine; and
• teriflunomide or a pharmaceutically acceptable salt thereof; and b) monitoring the blood pressure of the patient during the treatment.
• the method of managing the risk of high blood pressure can further comprise a step of administering to the patient a drug which is known to be effective for treating hypertension, when hypertension is diagnosed during the treatment.
• Another embodiment of the invention is related to a method for treating multiple sclerosis in a patient having multiple sclerosis and an active acute or chronic infection in need thereof, comprising:
• Another embodiment of the invention is related to a method of managing the risk of a serious infection to allow an effective and safe use of teriflunomide or a pharmaceutically acceptable salt thereof in the treatment of multiple sclerosis in a patient in need thereof comprising:
• Another embodiment of the invention is related to a method of managing the risk of a bone marrow disorder to allow an effective and safe use of teriflunomide or a pharmaceutically acceptable salt thereof in the treatment of multiple sclerosis in a patient in need thereof comprising:
• the method of maging the risk of a bone marrow disorder can further comprise a step that if neutropenia is diagnosed with the patient during the treatment with terilfunomide, the treatment should be considered to be suspended and optionally reinitiating the treatment after the CBC of the patient is back to normal level.
• Another embodiment of the invention is related to a method of managing the risk of polyneuropathy to allow an effective and safe use of teriflunomide or a
• teriflunomide or a pharmaceutically acceptable salt thereof if polyneuropathy is diagnosed during the treatment, then the treatment should be discontinued.
• a variety of educational materials may be employed to ensure proper prescribing, dispending and patient compliance according the methods described herein.
• a variety of literature and other material such as prescribing information, package inserts, medication guides, physician sheets, health care professional information sheets, medical journal advertisement, and product website may describe the risks and benefits of taking teriflunomide.
• liver enzymes should be monitored during the treatment with teriflunomide.
• a label or package insert contained within the packaging material indicating that if significant liver injury is confirmed or if the elevation of liver transaminases exceeds three times the upper limit of normal, then the treatment with teriflunomide should be discontinue.
• Another embodiment of the invention is related to an article of manufacture comprising:
• a label or package insert contained within the packaging material indicating that patients with an active acute or chronic infection should not start treatment with teriflunomide until the infection is resolved.
• a label or package insert contained within the packaging material indicating that if the patient develops a serious infection during the treatment, then the treatment should be suspended and the benefits and risks should be assessed prior to re-initiation of the treatment.
• Another embodiment of the invention is related to an article of manufacture comprising:
• a label or package insert contained within the packaging material indicating that teriflunomide should not be given to a patient who is hypersensitive to teriflunomide.
• Another embodiment of the invention is related to a package comprising teriflunomide or a pharmaceutically acceptable salt thereof, and a label, wherein the label comprises one or more messages selected from:
• liver enzymes should be monitored during the treatment with teriflunomide; b) if significant liver injury is confirmed or if the elevation of liver
• transaminases exceeds three times the upper limit of normal, then the treatment with teriflunomide should be discontinue;
• teriflunomide should be discontinued
• teriflunomide should not be given to a patient who is hypersensitive to
• Another embodiment of the invention is related to a method of promoting the use of teriflunomdie or a pharmaceutically acceptable salt thereof, comprising conveying to a recipient at least one message selected from:
• liver enzymes should be monitored during the treatment with teriflunomide; b) if significant liver injury is confirmed or if the elevation of liver
• transaminases exceeds three times the upper limit of normal, then the treatment with teriflunomide should be discontinue;
• teriflunomide should be discontinued
• teriflunomide should not be given to a patient who is hypersensitive to
• Another embodiment of the invention is related to a method of providing teriflunomide or a pharmaceutically acceptable salt thereof, wherein teriflunomide or the
• liver enzymes should be monitored during the treatment with teriflunomide; b) if significant liver injury is confirmed or if the elevation of liver transaminases exceeds three times the upper limit of normal, then the treatment with teriflunomide should be discontinue;
• teriflunomide should be discontinued
• teriflunomide should not be given to a patient who is hypersensitive to
• TEMSO Teiflunomide Multiple Sclerosis Oral trial
• TEMSO Phase III randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of teriflunomide in reducing the frequency of relapses and accumulation of physical disability in patients with RMS over 2 years.
• Patients eligible for enrolment were aged 18-55 years, met McDonald's criteria for MS diagnosis, and exhibited a relapsing clinical course, with or without progression. They were required to have a score of no more than 5.5 on the Kurtzke Expanded Disability Status Scale (EDSS), a minimum of two clinical relapses in the previous 2 years or one relapse during the preceding year, but no relapses in the 60 days before randomization. During the 4 weeks prior to randomization, patients were required to be clinically stable and have signed both the informed consent form and informed consent for HIV testing.
• EDSS Kurtzke Expanded Disability Status Scale
• cladribine Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate or mycophenolate
• Contraindication for MRI including presence of pacemaker, metallic implants in high-risk areas (e.g. artificial heart valves, aneurysm/vessel clips), presence of metallic material (e.g. shrapnel) in high-risk areas, known history of allergy to any contrast medium, or history of claustrophobia that would prevent completion of all protocol-scheduled MRI visits; hip implants were not contraindicated
• high-risk areas e.g. artificial heart valves, aneurysm/vessel clips
• metallic material e.g. shrapnel
• Hypoproteinemia e.g. in case of severe liver disease or nephrotic syndrome
• serum albumin ⁇ 3.0 g/dL
• a treatment neurologist at each site was responsible for evaluating patient eligibility, supervision of study medication administration, recording and treating adverse events and assessing relapses, and monitoring safety assessments.
• MRI scans were performed at baseline and Weeks 24, 48, 72 and 108, and conducted according to the study protocol; image data were collected at clinical site MRI facilities.
• the primary study objective was to determine the effect of teriflunomide in reducing annualized relapse rate (ARR; the number of confirmed relapses per patient-year).
• a relapse was defined as the appearance of a new clinical sign or symptom or clinical worsening of a previous sign or symptom that had been stable for at least 30 days and persisted for a minimum of 24 hours in the absence of fever.
• the key secondary endpoint was to determine the effect of teriflunomide on delaying disability progression at Week 108 as assessed by changes in EDSS. Sustained disability progression was defined as a persisting increase from baseline of at least 1 .0 point on the EDSS (or at least 0.5 for patients with a baseline EDSS score greater than 5.5) for at least 12 weeks.
• the key prespecified MRI endpoint was the effect of teriflunomide on burden of disease (total lesion volume).
• Other MRI endpoints included number of gadolinium (Gd)-enhancing T1 lesions, volume of T1 hypointense lesion components ('black holes'), number of unique active lesions and brain atrophy.
• Gd gadolinium
• FIS Fatigue Impact Scale
• Pulmonary symptoms suggestive of pulmonary toxicity were assessed by a pulmonologist using appropriate diagnostic testing.
• Neurologic symptoms suggestive of a peripheral neuropathy e.g. bilateral numbness, tingling of the feet or hands
• peripheral neuropathy e.g. bilateral numbness, tingling of the feet or hands
• pancreatic enzymes Laboratory testing of pancreatic enzymes was performed at baseline, then every 2 weeks for the first 24 weeks of treatment and every 6 weeks thereafter. An abdominal ultrasound was performed at baseline and then every 24 weeks until study completion. Any suspected abnormal ultrasound was followed up with a CT scan with contrast, or by MRI. Patients with any of the following adverse events were discontinued from the study and subsequently followed-up.
• Serum pregnancy testing was performed at baseline, Week 10, Week 24 and then every 12 weeks thereafter. If the pregnancy test was positive, the study medication was discontinued, and the physician was required to inform the patient of the risk of pregnancy and to discuss the potential alternatives. If the patient decided to continue with their pregnancy, a washout was required. If the patient decided not to continue with their pregnancy, the study medication could be resumed 2 weeks after termination of the pregnancy.
• RRR relative risk reductions
• ITT intention-to-treat
• Disability progression was analyzed using a log-rank test with time to first disability progression as the dependent variable, treatment as test variable, and region and baseline EDSS score as strata variables. Kaplan-Meier estimates and curves of the cumulative incidence were used to assess the rate of disability progression in patients across time points.
• the ITT population comprised randomized patients exposed to at least 1 day of study medication.
• a step-down testing procedure was used to analyze ARR and time to disability progression; the two doses of teriflunomide were compared sequentially with placebo.
• the ITT population was used for the analyses of all efficacy variables.
• the per-protocol population comprised the ITT population, excluding subjects with major efficacy-related protocol deviations and was used for the analysis of the primary efficacy variable and key secondary variables.
• a step-down testing procedure was used that compared teriflunomide with placebo in the following order: ARR, first in association with 14 mg teriflunomide, and next in association with 7 mg teriflunomide, followed by time to disability progression, first with 14 mg teriflunomide and next with 7 mg teriflunomide. Each test was performed only if the preceding evaluation was significant at the 5% level.
• the MMRM model (mixed-effect model with repeated measures) included treatment, EDSS strata, region, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction as covariates.
• the percentage of patients free from lesions was analysed by a logistic regression model that included treatment, number of lesions at baseline, EDSS strata and region as covariates.
• the Poisson regression model included treatment, number of lesions at baseline, EDSS strata and region as covariates, and log-transformed number of scans as an offset variable.
• the change from baseline in fatigue impact scale (FIS) total score was analyzed using MMRM.
• Baseline demographics and disease characteristics are shown in Table 1 . Although the majority of patients had relapsing remitting MS, a subset of patients were diagnosed with secondary progressive and progressive relapsing MS. The overall MRI burden of disease was approximately 19 ml_, with 36.2% having enhancement(s) at baseline. Seventy-three percent of patients had not received any disease-modifying therapy (DMT) treatment during the 2 years prior to study entry.
• DMT disease-modifying therapy
• ALT >3x ULN was similar across treatment groups (6.7%, 6.3%, and 6.7%), for placebo, teriflunomide 7 mg and 14 mg, respectively.
• Three patients (one in each treatment group) had increased ALT >3x ULN and total bilirubin >2x ULN; all cases were considered as non drug-induced liver injuries with alternative explanations provided (Hepatitis C, Gallbladder problems and CMV infection, respectively).
• ALT >8x ULN and/or ALT >3x ULN with total bilirubin >3 mg/dL and/or any hepatic event with seriousness criterion occurred in all groups (2.5%, 1 .9%, and 2.5%, for placebo, teriflunomide 7 mg and 14 mg, respectively).
• the proportion of patients with TEAEs related to blood pressure increase was higher in the teriflunonnide groups compared with the placebo group (3.1 %, 5.4%, and 5.0% in the placebo, teriflunomide 7 mg and 14 mg groups, respectively).
• the average increase in systolic blood pressure was ⁇ 4 mmHg and diastolic blood pressure was ⁇ 2 mmHg, respectively. No patient discontinued treatment due to increased blood pressure.
• TEAEs treatment- emergent adverse events
• *Burden of disease is defined as the total volumes of hyperintense T2 lesion component plus hypointense T1 lesion component on MRI.
• Burden of disease is defined as the total volumes of hyperintense on T2 lesion component plus hypointense on T1 lesion component as measured by MRI scan.
• CI confidence intervals
• Gd gadolinium
• LS least square
• SE standard error
• ITT intention to treat
• MMRM mixed-effect model with repeated measures
• Treatment-emergent adverse events (TEAEs) by Medical Dictionary for Regulatory Activities (MedDRA) preferred term >10% in any group, ranked by decreasing order in the teriflunomide 14 mg group
• ⁇ MedDRA preferred term alopecia
• Gastroenteritis 2 (0.6%) 0 1 (0.3%)
• Herpes zoster 1 (0.3%) 0 0
• Thyroid cancer 1 (0.3%) 0 0
• Hepatic enzyme increased 0 0 1 (0.3%)
• HLGT ⁇ exocrine pancreas conditions
• HLT enzymes
• SMQs standardized MedDRA queries
• MedDRA Medical Dictionary for Regulatory Activities
• TEAEs treatment-emergent adverse events

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