LaGanke1
Supplemental Appendix
SupplementalAppendix
MS ID# NEURIMMINFL/2016/011106
Safety/tolerability of the anti-Semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial
Materials and Methods
Placebo
The placebo used in the study matched the vialed VX15/2503 in that the vial, vial stopper and overseal, formulation, vial fill volume and label appearance were identical to that of the vialed antibody.
PD Assays
A validated assay was employed to determine cSEMA4D expression and VX15/2503-cSEMA4D saturation levels on peripheral blood T lymphocytes collected at PK time points. The details of this assay were previously described (16, 20) and are summarized here.
Two mL of whole blood was washed with PBS and resuspended in one mL of staining buffer. One hundred microliters of washed whole blood were dispensed into each of five polystyrene tubes and incubated with 100µL of VX15/2503 (20 µg/mL), or 100 µL staining buffer for 30 min at 4ºC. Treated cells were then washed with staining buffer and incubated 30 min at 4ºC with either 100 µL of mouse anti-chicken IgG biotin (10 µg/mL), 100 µL of mouse anti-human IgG4-Biotin (10 µg/mL), 100 mL of antibody 2269 biotin (5 µg/mL), or 100 mL of antibody 2282 biotin (5 µg/mL). Samples were then washed with staining buffer and incubated 30 min at 4ºC with a cocktail containing 5 µL anti-CD45 antibody V500, 0.25 mL anti-CD3 antibody AF488 and 20 µL strepavidinconjugated allophycocyanin. Samples were then incubated for 15 min at room temperature in 3 mL of flow cytometry lysing solution, washed with 2 mL PBS and resuspended in 0.5 mL PBS, and finally analyzed using a Becton DickinsonFACSCanto II.
Study Design
Primary, Secondary and Exploratory Study Objectives
The primary objective of this study wasto determine the safety and tolerability profile of singledose IV administration of VX15/2503 in patients with MS. The secondary objectives of the study were to characterize the singledose pharmacokinetics (PK)and immunogenicity of IV administration of VX15/2503 in patients with MS. Finally, the exploratory objectiveof this study was to characterize the pharmacodynamics (PD) of singledose IV administration of VX15/2503 in patients with MS.
Stopping Rules
Any occurrence of significant safety events described below required that further dosing of other patients be evaluated by the DESC, study medical monitor, and Sponsor’s medical representative to determine study discontinuation. Dose escalation was stopped if ANY of the criteria listed below were met. If the study was suspended due to meeting any of the criteria below, it could only be restarted after consultation with the FDA.
- The occurrence of 1 or more SAEs at any dose level that was deemed drug related (following unblinding of the study patient).
- The occurrence of a severe AE related to the study drug of similar origin in 2 or more patients within the same dose cohort.
- An elevation in 2 or more patients at a given dose level of any 1 of the following liver function parameters (confirmed by repeat sampling):
- ALT greater than 2.5 x ULN;
- Total bilirubin greater than 2.0 x the patient’s own baseline level on Day1 (admission), if above 1.5 x ULN;
- An increase in corrected QT interval (QTc) of 60 ms over baseline on 2consecutive days for ECG measurements or any QTc over 500 ms in 2 or more patients at a given dose level.
Safety Assessments - Adverse Events
The investigator was responsible for reporting all AEs that were observed or reported during the study, regardless of their relationship to study drug or their clinical significance. Nontreatment-emergent events that occurred during the screening period were only collected if related to a study screening procedure. Standard definitions were employed for AEs, TEAEs and SAEs; in addition, standard criteria were used in determining the relationship (if any) to study drug in causing or contributing to an adverse event.
Disease Activity Assessments
Efficacy was not formally evaluated in this study. However, exploratory assessments were performed using brain MRI results to assess any changes in MS disease activity. Baseline brain MRI (Gd-enhancing T1 and T2-weighted) was performed within 10days before dosing, and additional brain MRIs were performed on Day 29. All brain MRI scans were centrally analyzed. Exploratory assessments based on brain MRI data were the relationship between VX15/2503 dose level and the change in the following parameters from screening to day 29 postdose:
- Number of consensus gadolinium (Gd)-enhancing lesions
- Number of unenhancing T1 lesions (both new and existing)
- Number of T2 lesions (both existing and enlarging)
- Total volume of T1 and T2 lesions
Results
Baseline Characteristics
The demographic and baseline characteristics of the safety population are presented in Table 1S. Few patients had T1 Gd-enhancing lesions on MRI at screening (Table 2S, below). Overall, the median T2-weighted lesion volume for the study population was 4.6 mm3.
Previous MS treatment was reported for 47 patients (94%) in the overall study population. The most commonly reported treatments overall were glatiramer acetate (22patients, 44%), interferon beta-1b (19 patients, 38%), interferon beta 1a (Avonex®; 14patients, 28%), natalizumab (8 patients, 16%), and interferon beta-1a (Rebif®; 6patients, 12%). No analyses of the effects of prior MS treatments were conducted.
Pharmacokinetics and Pharmacodynamics
Previous work demonstrated that PBMC incubated with VX15/2503 did not result in cellular proliferation, cytokine release or an increase (versus baseline) in soluble SEMA4D levels (15). The increase in soluble SEMA4D levels noted following administration of VX15/2503 is due primarily to the increase in half-life of the VX15/2503-sSEMA4D complex versus that of the soluble ligand (15, 16, 20). Similar results have been published for secreted VEGF (22).
Brain MRI
MRI data for the exploratory population are presented in Table 3S, below. For brain MRI parameters, the actual values at Day 29 and change from screening to Day 29 were determined for the safety population. Few patients had T1 Gd-enhancing lesions on MRI at screening. The median T2-weighted lesion volume was 4.6 mm3for the study population overall; it was highest (17.6 mm3) in patients enrolled in the VX15/2503, 6 mg/kg cohort and lowest (1.1 mm3) in patients in the VX15/2503 10 mg/kg cohort (1.1 mm3).
LaGanke1
Supplemental Appendix
Supplemental Tables
Table 1S. Demographics and Baseline Characteristics of MS Patients Enrolled in the Safety and Tolerability Study of VX15/2503
VariableCategoryorStatistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40) / Total
(N = 50)
Gender [n (%)]
Female / 6 ( 60.0) / 6 ( 75.0) / 7 ( 87.5) / 5 ( 62.5) / 6 ( 75.0) / 5 ( 62.5) / 29 ( 72.5) / 35 ( 70.0)
Male / 4 ( 40.0) / 2 ( 25.0) / 1 ( 12.5) / 3 ( 37.5) / 2 ( 25.0) / 3 ( 37.5) / 11 ( 27.5) / 15 ( 30.0)
Race [n (%)]
White / 9 ( 90.0) / 5 ( 62.5) / 8 (100.0) / 8 (100.0) / 7 ( 87.5) / 7 ( 87.5) / 35 ( 87.5) / 44 ( 88.0)
Black / 1 ( 10.0) / 3 ( 37.5) / 0 ( 0.0) / 0 ( 0.0) / 1 ( 12.5) / 0 ( 0.0) / 4 ( 10.0) / 5 ( 10.0)
Asian / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0)
AmericanIndianor Alaska Native / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0)
NativeHawaiianor other Pacific Islander / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0)
Other / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 1 ( 12.5) / 1 ( 2.5) / 1 ( 2.0)
Ethnicity [n (%)]
HispanicorLatino / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 0 ( 0.0) / 1 ( 12.5) / 1 ( 2.5) / 1 ( 2.0)
NotHispanicor Latino / 10 (100.0) / 8 (100.0) / 8 (100.0) / 8 (100.0) / 8 (100.0) / 7 ( 87.5) / 39 ( 97.5) / 49 ( 98.0)
Age (years) at Enrollment
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 48.1 (10.8) / 41.6 (14.7) / 48.3 (5.8) / 47.3 (7.5) / 51.4 (5.2) / 45.0 (7.9) / 46.7 (9.1) / 47.0 (9.3)
Median / 52.0 / 37.0 / 48.5 / 49.0 / 51.5 / 45.0 / 48.0 / 48.0
Min,Max / 30, 60 / 22, 59 / 40, 59 / 31, 56 / 46, 59 / 32, 59 / 22, 59 / 22, 60
Height (cm) at Screening
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 174.42 (9.54) / 166.25 (11.99) / 164.64 (7.53) / 171.21 (10.34) / 167.50 (12.16) / 172.10 (4.94) / 168.34 (9.72) / 169.56 (9.90)
Median / 173.25 / 164.45 / 165.00 / 169.55 / 166.35 / 172.10 / 167.80 / 170.00
Min,Max / 162.6, 189.0 / 152.4, 190.5 / 154.0, 172.7 / 153.0, 185.0 / 154.9, 191.0 / 167.0, 182.0 / 152.4, 191.0 / 152.4, 191.0
Note:BMI=BodyMassIndex.
Source:Listing16.2.4,Dataset:[ADSL],Program:t_demog.sas,Output:T_14_1_2_demog.rtf,Generatedon:12MAY201508:17
Page1of2
Table 1S. Demographics and Baseline Characteristics of MS Patients Enrolled in the Safety and Tolerability Study of VX15/2503, continued
VariableCategoryorStatistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40) / Total
(N = 50)
Weight (kg) at Screening
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 77.45 (12.32) / 75.45 (16.62) / 73.71 (14.43) / 78.43 (17.31) / 80.14 (17.86) / 80.63 (12.61) / 77.67 (15.29) / 77.63 (14.63)
Median / 78.15 / 77.85 / 71.65 / 80.25 / 78.50 / 80.70 / 77.00 / 77.05
Min,Max / 58.9, 95.5 / 51.7, 105.1 / 58.1, 95.5 / 55.8, 103.0 / 59.5, 115.0 / 62.5, 97.0 / 51.7, 115.0 / 51.7, 115.0
BMI (kg/m2) at Screening
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 25.38 (3.05) / 26.98 (3.02) / 26.97 (3.22) / 26.52 (4.07) / 28.29 (3.47) / 27.39 (5.21) / 27.23 (3.72) / 26.86 (3.65)
Median / 25.24 / 27.86 / 25.80 / 25.15 / 29.50 / 27.74 / 27.64 / 26.50
Min,Max / 21.9, 31.7 / 22.3, 30.3 / 23.8, 32.0 / 20.8, 32.3 / 23.6, 32.1 / 21.3, 33.1 / 20.8, 33.1 / 20.8, 33.1
Note:BMI=BodyMassIndex.
Source:Listing16.2.4,Dataset:[ADSL],Program:t_demog.sas,Output:T_14_1_2_demog.rtf,Generatedon:12MAY201508:17
Page2of2
LaGanke1
Supplemental Appendix
Table 2S. Baseline MS Disease History and Disease Characteristics of Patients Enrolled in the Safety and Tolerability Study of VX15/2503
ParameterStatistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40) / Total
(N = 50)
Number of years since MS diagnosis
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 17.5 (9.8) / 13.1 (6.0) / 11.1 (6.3) / 10.8 (10.6) / 11.4 (5.1) / 9.9 (5.6) / 11.3 (6.7) / 12.5 (7.7)
Median / 16.0 / 14.5 / 11.0 / 7.5 / 12.0 / 10.5 / 11.0 / 12.0
Min,Max / 2, 40 / 4, 20 / 3, 23 / 2, 36 / 3, 17 / 3, 20 / 2, 36 / 2, 40
Number of relapses in the past 2 years
n / 1 / 6 / 3 / 3 / 0 / 4 / 16 / 17
Mean(SD) / 1.0 / 1.0 (0.0) / 1.0 (0.0) / 1.0 (0.0) / 1.3 (0.5) / 1.1 (0.3) / 1.1 (0.2)
Median / 1.0 / 1.0 / 1.0 / 1.0 / 1.0 / 1.0 / 1.0
Min,Max / 1, 1 / 1, 1 / 1, 1 / 1, 1 / 1, 2 / 1, 2 / 1, 2
Time since most recent relapse (yr)
n / 1 / 6 / 2 / 1 / 0 / 3 / 12 / 13
Mean(SD) / 2.0 / 0.7 (0.5) / 2.0 (0.0) / 1.0 / 0.7 (0.6) / 0.9 (0.7) / 1.0 (0.7)
Median / 2.0 / 1.0 / 2.0 / 1.0 / 1.0 / 1.0 / 1.0
Min,Max / 2, 2 / 0, 1 / 2, 2 / 1, 1 / 0, 1 / 0, 2 / 0, 2
Baseline EDSS
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 5.1 (1.7) / 4.4 (1.6) / 4.2 (1.3) / 3.8 (1.7) / 3.1 (2.0) / 3.4 (1.2) / 3.8 (1.6) / 4.0 (1.7)
Median / 6.0 / 4.0 / 3.5 / 3.5 / 2.3 / 3.8 / 3.5 / 3.5
Min,Max / 3, 7 / 3, 7 / 3, 7 / 2, 7 / 1, 6 / 2, 6 / 1, 7 / 1, 7
Note:MS=MultipleSclerosis;EDSS=ExpandedDisabilityStatusScale;MRI=MagneticResonanceImaging.
Source:Listings:16.2.6,16.2.14,Dataset:[ADQS,ADMH],Program:t_medhx.sas,Output:T_14_1_3_medhx.rtf,Generatedon:12MAY201508:19
Page1of3
LaGanke1
Supplemental Appendix
Table 2S. Baseline MS Disease History and Disease Characteristics of Patients Enrolled in the Safety and Tolerability Study of VX15/2503, continued
ParameterStatistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40) / Total
(N = 50)
Number of consensus T1 GD-enhancing lesions in MRI at screening
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 0.1 (0.3) / 0.5 (1.1) / 0.4 (1.1) / 0.3 (0.5) / 0.0 (0.0) / 1.4 (3.9) / 0.5 (1.8) / 0.4 (1.7)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / 0, 1 / 0, 3 / 0, 3 / 0, 1 / 0, 0 / 0, 11 / 0, 11 / 0, 11
T2-weighted Lesion Volume (mm3)
n / 9 / 8 / 8 / 8 / 8 / 8 / 40 / 49
Mean(SD) / 13.6 (10.7) / 8.7 (12.0) / 14.8 (22.4) / 14.7 (9.5) / 4.9 (8.6) / 10.7 (18.1) / 10.7 (14.8) / 11.3 (14.1)
Median / 12.7 / 2.4 / 4.3 / 17.6 / 1.1 / 2.9 / 4.3 / 4.6
Min,Max / 0, 29 / 0, 34 / 0, 67 / 0, 28 / 0, 25 / 0, 53 / 0, 67 / 0, 67
Number of T2-weighted lesions at screening
n / 9 / 8 / 8 / 8 / 8 / 8 / 40 / 49
Mean(SD) / 64.1 (36.5) / 34.0 (31.6) / 43.5 (25.6) / 62.9 (43.9) / 21.9 (15.3) / 31.8 (33.4) / 38.8 (32.9) / 43.4 (34.6)
Median / 62.0 / 19.5 / 47.0 / 55.0 / 19.0 / 17.0 / 26.5 / 39.0
Min,Max / 7, 127 / 12, 95 / 6, 71 / 1, 138 / 6, 45 / 2, 87 / 1, 138 / 1, 138
Unenhancing T1-weighted lesion volume (mm3)
n / 9 / 8 / 8 / 8 / 8 / 8 / 40 / 49
Mean(SD) / 5.9 (5.7) / 1.3 (2.9) / 7.3 (11.4) / 5.9 (6.2) / 1.8 (3.6) / 3.2 (5.8) / 3.9 (6.8) / 4.2 (6.6)
Median / 6.3 / 0.0 / 1.8 / 3.5 / 0.2 / 0.7 / 0.6 / 0.9
Min,Max / 0, 15 / 0, 8 / 0, 32 / 0, 15 / 0, 10 / 0, 17 / 0, 32 / 0, 32
Note:MS=MultipleSclerosis;EDSS=ExpandedDisabilityStatusScale;MRI=MagneticResonanceImaging.
Source:Listings:16.2.6,16.2.14,Dataset:[ADQS,ADMH],Program:t_medhx.sas,Output:T_14_1_3_medhx.rtf,Generatedon:12MAY201508:19
Page2of3
LaGanke1
Supplemental Appendix
Table 2S. Baseline MS Disease History and Disease Characteristics of Patients Enrolled in the Safety and Tolerability Study of VX15/2503, continued
ParameterStatistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40) / Total
(N = 50)
Number of unenhancing T1-weighted lesions at screening
n / 9 / 8 / 8 / 8 / 8 / 8 / 40 / 49
Mean(SD) / 55.2 (40.0) / 12.6 (22.5) / 30.3 (27.8) / 51.9 (50.4) / 13.1 (19.9) / 30.8 (41.7) / 27.7 (35.8) / 32.8 (37.7)
Median / 69.0 / 1.0 / 28.0 / 29.0 / 4.0 / 14.5 / 12.0 / 20.0
Min,Max / 2, 109 / 0, 58 / 1, 75 / 1, 142 / 0, 52 / 0, 118 / 0, 142 / 0, 142
Number of new/enhancing T2-weighted lesions at Day 29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 0.1 (0.3) / 0.4 (0.5) / 0.0 (0.0) / 0.1 (0.4) / 0.0 (0.0) / 4.1 (11.7) / 0.9 (5.2) / 0.8 (4.7)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / 0, 1 / 0, 1 / 0, 0 / 0, 1 / 0, 0 / 0, 33 / 0, 33 / 0, 33
Number of new T1-weighted lesions at Day 29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40 / 50
Mean(SD) / 0.0 (0.0) / 0.0 (0.0) / 0.0 (0.0) / 0.0 (0.0) / 0.0 (0.0) / 1.3 (3.5) / 0.3 (1.6) / 0.2 (1.4)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / 0, 0 / 0, 0 / 0, 0 / 0, 0 / 0, 0 / 0, 10 / 0, 10 / 0, 10
Note:MS=MultipleSclerosis;EDSS=ExpandedDisabilityStatusScale;MRI=MagneticResonanceImaging.
Source:Listings:16.2.6,16.2.14,Dataset:[ADQS,ADMH],Program:t_medhx.sas,Output:T_14_1_3_medhx.rtf,Generatedon:12MAY201508:19
Page3of3
LaGanke1
Supplemental Appendix
Table 3S. Change in Brain MRI Values from Screening to Day 29 for Patients Following Treatment with Placebo or VX15/2503
ParameterVisit
Statistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40)
ConsensusGD-enhancedlesion count
screening
n / 10 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 0.1 ( 0.3) / 0.5 ( 1.1) / 0.4 ( 1.1) / 0.3 ( 0.5) / 0.0 ( 0.0) / 1.4 ( 3.9) / 0.5 ( 1.8)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / 0, 1 / 0, 3 / 0, 3 / 0, 1 / 0, 0 / 0, 11 / 0, 11
Day29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 0.0 ( 0.0) / 0.6 ( 1.4) / 0.3 ( 0.7) / 0.1 ( 0.4) / 0.0 ( 0.0) / 3.4 ( 9.5) / 0.9 ( 4.3)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / 0, 0 / 0, 4 / 0, 2 / 0, 1 / 0, 0 / 0, 27 / 0, 27
Changefrombaseline to Day 29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / -0.1 ( 0.3) / 0.1 ( 1.6) / -0.1 ( 0.4) / -0.1 ( 0.4) / 0.0 ( 0.0) / 2.0 ( 5.7) / 0.4 ( 2.6)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / -1, 0 / -3, 3 / -1, 0 / -1, 0 / 0, 0 / 0, 16 / -3, 16
Note:BaselineisdefinedasDay1(Pre-dose)wherethedataisavailable.IfDay1dataismissing,thenScreeningdataisusedtocomputeChangeinBaseline.
Source:Listing16.2.14,Dataset:[ADQS],Program:t_bmri.sas,Output:T_14_2_4_bmri.rtf,Generatedon:12MAY201508:17
Page1of4
LaGanke1
Supplemental Appendix
Table 3S. Change in Brain MRI Values from Screening to Day 29 for Patients Following Treatment with Placebo or VX15/2503, continued
ParameterVisit
Statistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40)
T2-weightedlesionvolume (mm3)
screening
n / 9 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 13.6 (10.7) / 8.7 (12.0) / 14.8 (22.4) / 14.7 ( 9.5) / 4.9 ( 8.6) / 10.7 (18.1) / 10.7 (14.8)
Median / 12.7 / 2.4 / 4.3 / 17.6 / 1.1 / 2.9 / 4.3
Min,Max / 0, 29 / 0, 34 / 0, 67 / 0, 28 / 0, 25 / 0, 53 / 0, 67
Day29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 13.4 (10.0) / 8.6 (11.8) / 14.5 (22.0) / 14.4 ( 9.3) / 5.0 ( 9.0) / 11.2 (19.8) / 10.7 (15.0)
Median / 12.0 / 2.3 / 4.1 / 17.2 / 1.1 / 2.8 / 4.0
Min,Max / 0, 29 / 0, 33 / 0, 66 / 0, 26 / 0, 26 / 0, 58 / 0, 66
Changefrombaseline to Day 29
n / 9 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / -0.1 ( 0.8) / -0.1 ( 0.4) / -0.2 ( 0.4) / -0.3 ( 0.8) / 0.2 ( 0.4) / 0.5 ( 1.8) / -0.0 ( 0.9)
Median / 0.0 / -0.1 / -0.1 / -0.1 / 0.0 / -0.1 / 0.0
Min,Max / -2, 1 / -1, 0 / -1, 0 / -2, 1 / -0, 1 / -0, 5 / -2, 5
Note:BaselineisdefinedasDay1(Pre-dose)wherethedataisavailable.IfDay1dataismissing,thenScreeningdataisusedtocomputeChangeinBaseline.
Source:Listing16.2.14,Dataset:[ADQS],Program:t_bmri.sas,Output:T_14_2_4_bmri.rtf,Generatedon:12MAY201508:17
Page2of4
LaGanke1
Supplemental Appendix
Table 3S. Change in Brain MRI Values from Screening to Day 29 for Patients Following Treatment with Placebo or VX15/2503, continued
ParameterVisit
Statistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40)
T2-weightedlesioncount
screening
n / 9 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 64.1 (36.5) / 34.0 (31.6) / 43.5 (25.6) / 62.9 (43.9) / 21.9 (15.3) / 31.8 (33.4) / 38.8 (32.9)
Median / 62.0 / 19.5 / 47.0 / 55.0 / 19.0 / 17.0 / 26.5
Min,Max / 7, 127 / 12, 95 / 6, 71 / 1, 138 / 6, 45 / 2, 87 / 1, 138
UnenhancingT1-weightedlesion volume (mm3)
Screening
n / 9 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 5.9 ( 5.7) / 1.3 ( 2.9) / 7.3 (11.4) / 5.9 ( 6.2) / 1.8 ( 3.6) / 3.2 ( 5.8) / 3.9 ( 6.8)
Median / 6.3 / 0.0 / 1.8 / 3.5 / 0.2 / 0.7 / 0.6
Min,Max / 0, 15 / 0, 8 / 0, 32 / 0, 15 / 0, 10 / 0, 17 / 0, 32
Day29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 5.3 ( 5.5) / 1.2 ( 2.6) / 6.7 (10.2) / 5.8 ( 6.2) / 1.9 ( 4.0) / 3.1 ( 5.8) / 3.7 ( 6.3)
Median / 4.0 / 0.0 / 1.8 / 3.6 / 0.2 / 0.6 / 0.5
Min,Max / 0, 15 / 0, 8 / 0, 28 / 0, 15 / 0, 12 / 0, 17 / 0, 28
Changefrombaseline to Day 29
n / 9 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 0.0 ( 0.2) / -0.1 ( 0.3) / -0.6 ( 1.4) / -0.1 ( 0.2) / 0.1 ( 0.5) / -0.0 ( 0.1) / -0.1 ( 0.7)
Median / 0.0 / 0.0 / -0.1 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / -0, 0 / -1, 0 / -4, 0 / -0, 0 / -0, 1 / -0, 0 / -4, 1
Note:BaselineisdefinedasDay1(Pre-dose)wherethedataisavailable.IfDay1dataismissing,thenScreeningdataisusedtocomputeChangeinBaseline.
Source:Listing16.2.14,Dataset:[ADQS],Program:t_bmri.sas,Output:T_14_2_4_bmri.rtf,Generatedon:12MAY201508:17
Page3of4
LaGanke1
Supplemental Appendix
Table 3S. Change in Brain MRI Values from Screening to Day 29 for Patients Following Treatment with Placebo or VX15/2503, continued
ParameterVisit
Statistic / Placebo
(N = 10) / VX15/2503
1.0 mg/kg
(N = 8) / VX15/2503
3.0 mg/kg
(N = 8) / VX15/2503
6.0 mg/kg
(N = 8) / VX15/2503
10 mg/kg
(N = 8) / VX15/2503
20 mg/kg
(N = 8) / Total
VX15/2503
(N = 40)
UnenhancingT1-weightedlesion count
Screening
n / 9 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 55.2 (40.0) / 12.6 (22.5) / 30.3 (27.8) / 51.9 (50.4) / 13.1 (19.9) / 30.8 (41.7) / 27.7 (35.8)
Median / 69.0 / 1.0 / 28.0 / 29.0 / 4.0 / 14.5 / 12.0
Min,Max / 2, 109 / 0, 58 / 1, 75 / 1, 142 / 0, 52 / 0, 118 / 0, 142
New/EnlargingT2-weightedlesion count
Day29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 0.1 ( 0.3) / 0.4 ( 0.5) / 0.0 ( 0.0) / 0.1 ( 0.4) / 0.0 ( 0.0) / 4.1 (11.7) / 0.9 ( 5.2)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / 0, 1 / 0, 1 / 0, 0 / 0, 1 / 0, 0 / 0, 33 / 0, 33
UnenhancingNewT1-weighted lesion count
Day29
n / 10 / 8 / 8 / 8 / 8 / 8 / 40
Mean(SD) / 0.0 ( 0.0) / 0.0 ( 0.0) / 0.0 ( 0.0) / 0.0 ( 0.0) / 0.0 ( 0.0) / 1.3 ( 3.5) / 0.3 ( 1.6)
Median / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0 / 0.0
Min,Max / 0, 0 / 0, 0 / 0, 0 / 0, 0 / 0, 0 / 0, 10 / 0, 10
Note:BaselineisdefinedasDay1(Pre-dose)wherethedataisavailable.IfDay1dataismissing,thenScreeningdataisusedtocomputeChangeinBaseline.
Source:Listing16.2.14,Dataset:[ADQS],Program:t_bmri.sas,Output:T_14_2_4_bmri.rtf,Generatedon:12MAY201508:17
Page4of4