WARNING
RISK OF ANAPHYLAXIS
LIFE-THREATENING ANAPHYLACTIC REACTIONS HAVE OCCURRED IN SOME PATIENTS DURING VIMIZIM INFUSIONS. ANAPHYLAXIS, PRESENTING AS COUGH, ERYTHEMA, THROAT TIGHTNESS, URTICARIA, FLUSHING, CYANOSIS, HYPOTENSION, RASH, DYSPNEA, CHEST DISCOMFORT, AND GASTROINTESTINAL SYMPTOMS (E.G., NAUSEA, ABDOMINAL PAIN, RETCHING, AND VOMITING) IN CONJUNCTION WITH URTICARIA, HAVE BEEN REPORTED TO OCCUR DURING VIMIZIM INFUSIONS, REGARDLESS OF DURATION OF THE COURSE OF TREATMENT. CLOSELY OBSERVE PATIENTS DURING AND AFTER VIMIZIM ADMINISTRATION AND BE PREPARED TO MANAGE ANAPHYLAXIS. INFORM PATIENTS OF THE SIGNS AND SYMPTOMS OF ANAPHYLAXIS AND HAVE THEM SEEK IMMEDIATE MEDICAL CARE SHOULD SYMPTOMS OCCUR. PATIENTS WITH ACUTE RESPIRATORY ILLNESS MAY BE AT RISK OF SERIOUS ACUTE EXACERBATION OF THEIR RESPIRATORY COMPROMISE DUE TO HYPERSENSITIVITY REACTIONS, AND REQUIRE ADDITIONAL MONITORING [SEE WARNINGS AND PRECAUTIONS AND ADVERSE
INDICATIONS
VIMIZIM (ELOSULFASE ALFA) IS INDICATED FOR PATIENTS WITH MUCOPOLYSACCHARIDOSIS TYPE IVA (MPS IVA; MORQUIO A SYNDROME).
DOSAGE FORMS AND STRENGTHS
INJECTION: 5 MG/5 ML (1 MG/ML) IN SINGLE-USE VIALS.
STORAGE AND HANDLING
VIMIZIM IS SUPPLIED AS A CONCENTRATED SOLUTION FOR INFUSION (1 MG PER ML) REQUIRING DILUTION. ONE VIAL OF 5 ML CONTAINS 5 MG VIMIZIM.
NDC 68135-100-01, 5 ML VIAL
STORE VIMIZIM UNDER REFRIGERATION AT 2°C TO 8°C (36°F TO 46°F). DO NOT FREEZE OR SHAKE. PROTECT FROM LIGHT.
DILUTED VIMIZIM SHOULD BE USED IMMEDIATELY. IF IMMEDIATE USE IS NOT POSSIBLE, DILUTED VIMIZIM MAY BE STORED FOR UP TO 24 HOURS AT 2°C TO 8°C (36°F TO 46°F) FOLLOWED BY UP TO 24 HOURS AT 23°C TO 27°C (73°F TO 81°F) DURING ADMINISTRATION.
MANUFACTURED BY: BIOMARIN PHARMACEUTICAL INC. NOVATO, CA 94949. REVISED: FEB 2014
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSE
THE RECOMMENDED DOSE IS 2 MG PER KG GIVEN INTRAVENOUSLY OVER A MINIMUM RANGE OF 3.5 TO 4.5 HOURS, BASED ON INFUSION VOLUME, ONCE EVERY WEEK. PRE-TREATMENT WITH ANTIHISTAMINES WITH OR WITHOUT ANTIPYRETICS IS RECOMMENDED 30 TO 60 MINUTES PRIOR TO THE START OF THE INFUSION [SEE WARNINGS AND PRECAUTIONS].
PARENTERAL DRUG PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION, WHENEVER SOLUTION AND CONTAINER PERMIT.
PREPARATION INSTRUCTIONS
IMPORTANT INFORMATION: THIS PRODUCT SHOULD BE PREPARED AND ADMINISTERED UNDER THE SUPERVISION OF A HEALTHCARE PROFESSIONAL WITH THE ABILITY TO MANAGE MEDICAL EMERGENCIES.
DETERMINE THE NUMBER OF VIALS TO BE DILUTED BASED ON THE INDIVIDUAL PATIENT'S WEIGHT AND THE RECOMMENDED DOSE OF 2 MG/KG.
DILUTE THE CALCULATED DOSE TO A FINAL VOLUME OF 100 ML OR 250 ML USING 0.9% SODIUM CHLORIDE INJECTION, USP.
THE FINAL VOLUME IS BASED ON THE PATIENT'S WEIGHT AS FOLLOWS:
" FOR PATIENTS WHO WEIGH LESS THAN 25 KG, THE FINAL VOLUME SHOULD BE 100 ML;
" FOR PATIENTS WHO WEIGH 25 KG OR MORE, THE FINAL VOLUME SHOULD BE 250 ML.
THE SOLUTION SHOULD BE CLEAR TO SLIGHTLY OPALESCENT AND COLORLESS TO PALE YELLOW WHEN DILUTED. DO NOT USE IF THE SOLUTION IS DISCOLORED OR IF THERE IS PARTICULATE MATTER IN THE SOLUTION. NOTE THAT A DILUTED SOLUTION WITH SLIGHT FLOCCULATION (E.G., THIN TRANSLUCENT FIBERS) IS ACCEPTABLE FOR ADMINISTRATION.
AVOID AGITATION DURING PREPARATION. GENTLY ROTATE THE BAG TO ENSURE PROPER DISTRIBUTION. DO NOT SHAKE THE SOLUTION.
ADMINISTRATION INSTRUCTIONS
ADMINISTER THE DILUTED SOLUTION TO PATIENTS USING A LOW-PROTEIN BINDING INFUSION SET EQUIPPED WITH A LOW-PROTEIN BINDING 0.2 MICROMETER (?M) IN-LINE FILTER.
NOTE: THE SAFETY AND EFFECTIVENESS OF VIMIZIM HAVE NOT BEEN ESTABLISHED IN PEDIATRIC PATIENTS LESS THAN 5 YEARS OF AGE [SEE USE IN SPECIFIC POPULATIONS].
FOR PATIENTS WHO WEIGH LESS THAN 25 KG: INITIAL INFUSION RATE SHOULD BE 3 ML PER HOUR FOR THE FIRST 15 MINUTES AND, IF TOLERATED, INCREASED TO 6 ML PER HOUR FOR THE NEXT 15 MINUTES. IF THIS RATE IS TOLERATED, THEN THE RATE MAY BE INCREASED EVERY 15 MINUTES IN 6 ML PER HOUR INCREMENTS, NOT TO EXCEED 36 ML PER HOUR. THE TOTAL VOLUME OF THE INFUSION SHOULD BE DELIVERED OVER A MINIMUM OF 3.5 HOURS.
FOR PATIENTS WHO WEIGH 25 KG OR MORE: INITIAL INFUSION RATE SHOULD BE 6 ML PER HOUR FOR THE FIRST 15 MINUTES AND, IF TOLERATED, THE INFUSION RATE MAY BE INCREASED TO 12 ML PER HOUR FOR THE NEXT 15 MINUTES. IF THIS RATE IS TOLERATED, THEN THE RATE MAY BE INCREASED EVERY 15 MINUTES IN 12 ML PER HOUR INCREMENTS, NOT TO EXCEED 72 ML PER HOUR. THE TOTAL VOLUME OF THE INFUSION SHOULD BE DELIVERED OVER A MINIMUM OF 4.5 HOURS.
THE INFUSION RATE MAY BE SLOWED, TEMPORARILY STOPPED, OR DISCONTINUED FOR THAT VISIT IN THE EVENT OF HYPERSENSITIVITY REACTIONS [SEE WARNINGS AND PRECAUTIONS]. DO NOT INFUSE WITH OTHER PRODUCTS IN THE INFUSION TUBING. COMPATIBILITY WITH OTHER PRODUCTS HAS NOT BEEN EVALUATED.
STORAGE AND STABILITY
VIMIZIM DOES NOT CONTAIN PRESERVATIVES; THEREFORE THE PRODUCT SHOULD BE USED IMMEDIATELY AFTER DILUTION. IF IMMEDIATE USE IS NOT POSSIBLE, THE DILUTED PRODUCT MAY BE STORED FOR UP TO 24 HOURS AT 2°C TO 8°C (36°F TO 46°F) FOLLOWED BY UP TO 24 HOURS AT 23°C TO 27°C (73°F TO 81°F). ADMINISTRATION OF VIMIZIM SHOULD BE COMPLETED WITHIN 48 HOURS FROM THE TIME OF DILUTION. VIALS ARE FOR SINGLE-USE ONLY. DISCARD ANY UNUSED PRODUCT. DO NOT FREEZE OR SHAKE. PROTECT FROM LIGHT.
SIDE EFFECTS
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
THE FOLLOWING SERIOUS ADVERSE REACTIONS ARE DESCRIBED BELOW AND ELSEWHERE IN THE LABELING:
" ANAPHYLAXIS AND HYPERSENSITIVITY REACTIONS [SEE WARNINGS AND PRECAUTIONS].
THE MOST COMMON ADVERSE REACTIONS ( ? 10%) OBSERVED ACROSS PRE-MARKETING CLINICAL TRIALS WERE SIMILAR IN TYPE AND FREQUENCY AS THOSE OBSERVED IN THE PLACEBO-CONTROLLED TRIAL (SEE TABLE1). THE ACUTE REACTIONS REQUIRING INTERVENTION WERE MANAGED BY EITHER TEMPORARILY INTERRUPTING OR DISCONTINUING INFUSION, AND ADMINISTERING ADDITIONAL ANTIHISTAMINE, ANTIPYRETICS, OR CORTICOSTEROIDS.
CLINICAL TRIALS EXPERIENCE
A 24-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL OF VIMIZIM WAS CONDUCTED IN 176 PATIENTS WITH MPS IVA, AGES 5 TO 57 YEARS OLD. APPROXIMATELY HALF OF THE PATIENTS (49%) WERE MALE. OF THE 176 PATIENTS, 65% WERE WHITE, 23% ASIAN, 3% BLACK, AND 10% OTHER RACE. THE MAJORITY OF PATIENTS (78%) WERE NON-HISPANIC. PATIENTS WERE RANDOMIZED TO THREE TREATMENT GROUPS: VIMIZIM 2 MG/KG ONCE PER WEEK (N=58), VIMIZIM 2 MG/KG ONCE EVERY OTHER WEEK (N=59), OR PLACEBO (N=59). ALL PATIENTS WERE TREATED WITH ANTIHISTAMINES PRIOR TO EACH INFUSION.
TABLE 1 SUMMARIZES THE MOST COMMON ADVERSE REACTIONS THAT OCCURRED IN THE PLACEBO-CONTROLLED TRIAL WITH AN INCIDENCE OF ? 10% IN PATIENTS TREATED WITH VIMIZIM 2 MG/KG ONCE PER WEEK AND WITH A HIGHER INCIDENCE THAN IN THE PLACEBO-TREATED PATIENTS.
TABLE 1: ADVERSE REACTIONS THAT OCCURRED IN THE PLACEBO-CONTROLLED TRIAL IN AT LEAST 10% OF PATIENTS IN THE VIMIZIM 2 MG/KG ONCE PER WEEK GROUP AND WITH A HIGHER INCIDENCE THAN IN THE PLACEBO GROUP
ADVERSE REACTION VIMIZIM 2 MG/KG ONCE PER WEEK
N= 58
N (%) PLACEBO
N= 59
N (%)
PYREXIA 19 (33%) 8 (14%)
VOMITING 18 (31%) 4 (7%)
HEADACHE 15 (26%) 9 (15%)
NAUSEA 14 (24%) 4 (7%)
ABDOMINAL PAIN 12 (21%) 1 (1.7%)
CHILLS 6 (10.3%) 1 (1.7%)
FATIGUE 6 (10.3%) 2 (3.4%)
EXTENSION TRIAL
AN OPEN-LABEL EXTENSION TRIAL WAS CONDUCTED IN 173 PATIENTS WHO COMPLETED THE PLACEBO-CONTROLLED TRIAL [SEE CLINICAL STUDIES]. NO NEW ADVERSE REACTIONS WERE REPORTED.
IMMUNOGENICITY
AS WITH ALL THERAPEUTIC PROTEINS, THERE IS POTENTIAL FOR IMMUNOGENICITY. ALL PATIENTS TREATED WITH VIMIZIM 2 MG/KG ONCE PER WEEK IN THE PLACEBO-CONTROLLED TRIAL DEVELOPED ANTI-DRUG ANTIBODIES BY WEEK 4. ANTI-DRUG ANTIBODY TITERS WERE SUSTAINED OR INCREASED FOR THE DURATION OF VIMIZIM TREATMENT. BECAUSE ALL PATIENTS DEVELOPED ANTI-DRUG ANTIBODIES, ASSOCIATIONS BETWEEN ANTIBODY TITERS AND REDUCTIONS IN TREATMENT EFFECT OR THE OCCURRENCE OF ANAPHYLAXIS OR OTHER HYPERSENSITIVITY REACTIONS COULD NOT BE DETERMINED.
ALL PATIENTS TREATED WITH VIMIZIM 2 MG/KG ONCE PER WEEK TESTED POSITIVE FOR NEUTRALIZING ANTIBODIES CAPABLE OF INHIBITING THE DRUG FROM BINDING TO THE MANNOSE-6-PHOSPHATE RECEPTOR AT LEAST ONCE DURING THE TRIAL. BINDING TO THIS RECEPTOR IS REQUIRED FOR VIMIZIM TO BE TAKEN INTO CELLS WHERE IT IS ACTIVE. NEUTRALIZING ANTIBODY TITERS WERE NOT DETERMINED IN THE PATIENTS. THEREFORE, THE POSSIBILITY OF AN ASSOCIATION BETWEEN NEUTRALIZING ANTIBODY TITER AND TREATMENT EFFECT CANNOT BE ASSESSED.
ASSESSMENT OF THE INCIDENCE OF ANTIBODY FORMATION IS HIGHLY DEPENDENT ON THE SENSITIVITY AND SPECIFICITY OF THE ASSAY. ADDITIONALLY, THE OBSERVED INCIDENCE OF ANTIBODY (INCLUDING NEUTRALIZING ANTIBODY) POSITIVITY IN AN ASSAY MAY BE INFLUENCED BY SEVERAL FACTORS INCLUDING ASSAY METHODOLOGY, SAMPLE HANDLING, TIMING OF SAMPLE COLLECTION, CONCOMITANT MEDICATIONS, AND UNDERLYING DISEASE. FOR THESE REASONS, COMPARISON OF THE INCIDENCE OF ANTIBODIES TO VIMIZIM WITH THE INCIDENCE OF ANTIBODIES TO OTHER PRODUCTS MAY BE MISLEADING.
READ THE VIMIZIM (ELOSULFASE ALFA INJECTION FOR INTRAVENOUS USE) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
MUCOPOLYSACCHARIDOSES COMPRISE A GROUP OF LYSOSOMAL STORAGE DISORDERS CAUSED BY THE DEFICIENCY OF SPECIFIC LYSOSOMAL ENZYMES REQUIRED FOR THE CATABOLISM OF GLYCOSAMINOGLYCANS (GAG). MUCOPOLYSACCHARIDOSIS IVA (MPS IVA, MORQUIO A SYNDROME) IS CHARACTERIZED BY THE ABSENCE OR MARKED REDUCTION IN N-ACETYLGALACTOSAMINE-6-SULFATASE ACTIVITY. THE SULFATASE ACTIVITY DEFICIENCY RESULTS IN THE ACCUMULATION OF THE GAG SUBSTRATES, KS AND C6S, IN THE LYSOSOMAL COMPARTMENT OF CELLS THROUGHOUT THE BODY. THE ACCUMULATION LEADS TO WIDESPREAD CELLULAR, TISSUE, AND ORGAN DYSFUNCTION. VIMIZIM IS INTENDED TO PROVIDE THE EXOGENOUS ENZYME N-ACETYLGALACTOSAMINE-6-SULFATASE THAT WILL BE TAKEN UP INTO THE LYSOSOMES AND INCREASE THE CATABOLISM OF THE GAGS KS AND C6S. ELOSULFASE ALFA UPTAKE BY CELLS INTO LYSOSOMES IS MEDIATED BY THE BINDING OF MANNOSE-6-PHOSPHATE-TERMINATED OLIGOSACCHARIDE CHAINS OF ELOSULFASE ALFA TO MANNOSE-6-PHOSPHATE RECEPTORS.
IN THE ABSENCE OF AN ANIMAL DISEASE MODEL THAT RECAPITULATES THE HUMAN DISEASE PHENOTYPE, ELOSULFASE ALFA PHARMACOLOGICAL ACTIVITY WAS EVALUATED USING HUMAN PRIMARY CHONDROCYTES FROM TWO MPS IVA PATIENTS. TREATMENT OF MPS IVA CHONDROCYTES WITH ELOSULFASE ALFA INDUCED CLEARANCE OF KS LYSOSOMAL STORAGE FROM THE CHONDROCYTES.
PHARMACODYNAMICS
THE PHARMACODYNAMIC EFFECT OF VIMIZIM WAS ASSESSED BY REDUCTIONS IN URINARY KS LEVELS. THE RELATIONSHIP OF URINARY KS TO OTHER MEASURES OF CLINICAL RESPONSE HAS NOT BEEN ESTABLISHED [SEE CLINICAL STUDIES]. NO ASSOCIATION WAS OBSERVED BETWEEN ANTIBODY DEVELOPMENT AND URINARY KS LEVELS.
PHARMACOKINETICS
THE PHARMACOKINETICS OF ELOSULFASE ALFA WERE EVALUATED IN 23 PATIENTS WITH MPS IVA WHO RECEIVED INTRAVENOUS INFUSIONS OF VIMIZIM 2 MG/KG ONCE WEEKLY, OVER APPROXIMATELY 4 HOURS, FOR 22 WEEKS. ELEVEN PATIENTS WERE AGED 5 TO 11 YEARS, SIX WERE AGED 12 TO 17 YEARS, AND SIX WERE AGED 18 TO 41 YEARS. TABLE 2 SUMMARIZES THE PHARMACOKINETIC PARAMETERS AT WEEK 0 AND WEEK 22. MEAN AUC0-T AND CMAX INCREASED TO 2.8- AND 2.9-FOLD, RESPECTIVELY, AT WEEK 22 COMPARED TO WEEK 0. MEAN T½INCREASED FROM 7.5 MIN AT WEEK 0 TO 35.9 MIN AT WEEK 22. THESE CHANGES ARE LIKELY RELATED TO THE DEVELOPMENT OF NEUTRALIZING ANTIBODIES IN ALL PATIENTS.
TABLE 2: PHARMACOKINETIC PARAMETERS
PHARMACOKINETIC PARAMETER WEEK 0
(N = 22)* MEAN (SD) WEEK 22
(N = 22)* MEAN (SD)
AUC0-T, MIN X ?G/ML† 238 (100) 577 (416)
CMAX, ?G/ML‡ 1.49 (0.534) 4.04 (3.24)
TMAX, MIN§ 172 (75.3) 202 ( 90.8)
CL, ML/MIN/KG
10.0 (3.73)# 7.08 (13.0)?
VDSS, ML/KG? 396 (316) ? 650 (1842) ?
T½, MIN? 7.52 (5.48) # 35.9 (21.5)?
* THE PHARMACOKINETICS OF ELOSULFASE ALFA WAS EVALUATED IN 23 INDIVIDUAL PATIENTS. HOWEVER, 1 PATIENT WAS NOT TESTED AT WEEK 0 AND ANOTHER PATIENT WAS NOT TESTED AT WEEK 22.
†AUC0-T, AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE FROM TIME ZERO TO THE TIME OF LAST MEASURABLE CONCENTRATION;
‡CMAX, OBSERVED MAXIMUM PLASMA CONCENTRATION;
§ TMAX, TIME FROM ZERO TO MAXIMUM PLASMA CONCENTRATION;
CL, TOTAL CLEARANCE OF DRUG AFTER INTRAVENOUS ADMINISTRATION;
#N = 15;
?N = 20
?VDSS, APPARENT VOLUME OF DISTRIBUTION AT STEADY-STATE;
?N = 14;
? T½, ELIMINATION HALF-LIFE
CLINICAL STUDIES
THE SAFETY AND EFFICACY OF VIMIZIM WERE ASSESSED IN A 24-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL OF 176 PATIENTS WITH MPS IVA. THE AGE OF PATIENTS RANGED FROM 5 TO 57 YEARS. THE MAJORITY OF THE PATIENTS (82%) PRESENTED WITH A MEDICAL HISTORY OF MUSCULOSKELETAL CONDITIONS, WHICH INCLUDES KNEE DEFORMITY (52%), KYPHOSIS (31%), HIP DYSPLASIA (22%), PRIOR SPINAL FUSION SURGERY (22%) AND ARTHRALGIA (20%). AT BASELINE, ALL ENROLLED PATIENTS COULD WALK MORE THAN 30 METERS (M) BUT LESS THAN 325 M IN SIX MINUTES.
PATIENTS RECEIVED VIMIZIM 2 MG/KG ONCE PER WEEK (N=58), VIMIZIM 2 MG/KG ONCE EVERY OTHER WEEK (N=59), OR PLACEBO (N=59).
THE PRIMARY ENDPOINT WAS THE CHANGE FROM BASELINE IN THE DISTANCE WALKED IN SIX MINUTES (SIX MINUTE WALK TEST, 6-MWT) AT WEEK 24. THE OTHER ENDPOINTS INCLUDED CHANGES FROM BASELINE IN THE RATE OF STAIR CLIMBING IN THREE MINUTES (THREE-MINUTE STAIR CLIMB TEST, 3-MSCT) AND CHANGES FROM BASELINE IN URINE KS LEVELS AT WEEK 24. THE TREATMENT EFFECT IN THE DISTANCE WALKED IN 6 MINUTES, COMPARED TO PLACEBO, WAS 22.5 M (CI95, 4.0, 40.9; P=0.0174) IN PATIENTS WHO RECEIVED VIMIZIM 2 MG/KG ONCE PER WEEK. THERE WAS NO DIFFERENCE IN THE RATE OF STAIR CLIMBING BETWEEN PATIENTS WHO RECEIVED VIMIZIM 2 MG/KG ONCE PER WEEK AND THOSE WHO RECEIVED PLACEBO. PATIENTS WHO RECEIVED VIMIZIM 2 MG/KG ONCE EVERY OTHER WEEK PERFORMED SIMILARLY IN THE 6-MWT AND 3-MSCT AS THOSE WHO RECEIVED PLACEBO. THE REDUCTION IN URINARY KS LEVELS FROM BASELINE, A MEASURE OF PHARMACODYNAMIC EFFECT, WAS GREATER IN THE VIMIZIM TREATMENT GROUPS COMPARED TO PLACEBO. THE RELATIONSHIP BETWEEN URINARY KS AND OTHER MEASURES OF CLINICAL RESPONSE HAS NOT BEEN ESTABLISHED.
TABLE 3: RESULTS FROM PLACEBO-CONTROLLED CLINICAL TRIAL
EXTENSION TRIAL
PATIENTS WHO PARTICIPATED IN THE PLACEBO-CONTROLLED TRIAL WERE ELIGIBLE TO CONTINUE TREATMENT IN AN OPEN-LABEL EXTENSION TRIAL. ONE HUNDRED SEVENTY-THREE OF 176 PATIENTS ENROLLED IN THE EXTENSION TRIAL IN WHICH PATIENTS RECEIVED VIMIZIM 2 MG/KG ONCE PER WEEK (N=86) OR VIMIZIM 2 MG/KG ONCE EVERY OTHER WEEK (N=87). IN PATIENTS WHO CONTINUED TO RECEIVE VIMIZIM 2 MG/KG ONCE PER WEEK FOR ANOTHER 48 WEEKS (FOR A TOTAL OF 72-WEEK EXPOSURE), WALKING ABILITY SHOWED NO FURTHER IMPROVEMENT BEYOND THE FIRST 24 WEEKS OF TREATMENT IN THE PLACEBO-CONTROLLED TRIAL.