MS Fumarates

Authors

Josh DeClercq

Department of Biostatistics

Vanderbilt University Medical Center

Published

May 15, 2024

1 Study Overview

1.1 Outcomes

Evaluate the occurrence and severity of lymphopenia in those that transitioned

  • Baseline 

    • Closest lab prior to switch (within 6 months) 

  • Measured 18 months post-switch

    • Lowest ALC during time period  
    • % reduction from baseline (use lowest ALC during time period) 

  • Identify patient characteristics that may explain change in lymphocyte counts 

2 Descriptive statistics

2.1 Patient information

Characteristic N Vumerity, N = 791 Bafiertam, N = 151 Overall, N = 941
Sex 94


    Female
61 (77.2%) 14 (93.3%) 75 (79.8%)
    Male
18 (22.8%) 1 (6.67%) 19 (20.2%)
Race 94


    White
60 (75.9%) 11 (73.3%) 71 (75.5%)
    Black or African American
15 (19.0%) 2 (13.3%) 17 (18.1%)
    American Indian or Alaska Native
1 (1.27%) 0 (0%) 1 (1.06%)
    Decline to Answer
2 (2.53%) 1 (6.67%) 3 (3.19%)
    Unknown
1 (1.27%) 1 (6.67%) 2 (2.13%)
Ethnicity 94


    Not Hispanic, Latino/a, or Spanish origin
72 (91.1%) 15 (100.0%) 87 (92.6%)
    Unknown
1 (1.27%) 0 (0%) 1 (1.06%)
    Decline to Answer
4 (5.06%) 0 (0%) 4 (4.26%)
    Other Hispanic, Latino/a, or Spanish origin
1 (1.27%) 0 (0%) 1 (1.06%)
    Null
1 (1.27%) 0 (0%) 1 (1.06%)
Number of previous DMTs 93


    0
32 (41.0%) 4 (26.7%) 36 (38.7%)
    1
28 (35.9%) 5 (33.3%) 33 (35.5%)
    1 ("injection that caused elevated LFTs" - IFN?)
1 (1.28%) 0 (0%) 1 (1.08%)
    2
13 (16.7%) 4 (26.7%) 17 (18.3%)
    3
2 (2.56%) 1 (6.67%) 3 (3.23%)
    4
2 (2.56%) 0 (0%) 2 (2.15%)
    5
0 (0%) 1 (6.67%) 1 (1.08%)
    Missing
1 0 1
Does the patient have outside labs that need to be reviewed? 94


    No
35 (44.3%) 6 (40.0%) 41 (43.6%)
    Yes
44 (55.7%) 9 (60.0%) 53 (56.4%)
1 n (%)

2.2 BMI

Using the BMI closest to the date of switch within one year in either direction.

Characteristic N Vumerity, N = 79 Bafiertam, N = 15 Overall, N = 94
BMI 92


    Mean (SD)
29.7 (5.9) 27.8 (7.7) 29.4 (6.2)
    Median (IQR)
29.5 (25.6 - 33.4) 25.2 (22.2 - 33.7) 29.1 (25.3 - 33.4)
    Range
17.5 - 50.5 18.5 - 44.9 17.5 - 50.5
    Missing
1 1 2
Time from switch date to BMI (days) 92


    Mean (SD)
-11.9 (101.1) -14.6 (54.3) -12.3 (95.2)
    Median (IQR)
-6.5 (-54.3 - 40.5) -17.5 (-47.8 - 9.5) -7.0 (-50.8 - 37.5)
    Range
-327.0 - 218.0 -104.0 - 78.0 -327.0 - 218.0
    Missing
1 1 2
Height (cm) 92


    Mean (SD)
168.0 (8.6) 166.3 (6.5) 167.8 (8.3)
    Median (IQR)
167.6 (162.6 - 172.7) 165.1 (162.6 - 169.5) 167.6 (162.6 - 172.7)
    Range
149.9 - 185.4 154.9 - 182.9 149.9 - 185.4
    Missing
1 1 2
Weight (kg) 92


    Mean (SD)
84.0 (18.8) 76.4 (19.3) 82.8 (19.0)
    Median (IQR)
82.3 (71.9 - 91.3) 67.4 (64.2 - 91.3) 81.6 (68.7 - 91.4)
    Range
47.7 - 155.0 53.6 - 118.6 47.7 - 155.0
    Missing
1 1 2

2.3 Previous DMT

2.3.1 Patient level

Characteristic N = 941
Copaxone (Glatiramer or Glatopa) 24 (25.5%)
Rebif 20 (21.3%)
Avonex 15 (16.0%)
Betaseron (or Extavia) 11 (11.7%)
Tysabri 9 (9.57%)
Gilenya 7 (7.45%)
Aubagio 4 (4.26%)
Novantrone 2 (2.13%)
Plegridy 2 (2.13%)
Tecfidera 1 (1.06%)
[Zero selected] 37 (39.4%)
1 n (%)

2.4 Medication information

Characteristic N N = 941
Time taking Tecfidera before switching to Vumerity or Baferitam (months) 94
    Mean (SD)
49.0 (31.8)
    Median (IQR)
47.9 (21.4 - 75.4)
    Range
1.1 - 113.6
Was there a gap between Tecfidera and switching to the other fumarate? 91
    No
80 (87.9%)
    Yes
11 (12.1%)
    Missing
3
Which medication did the patient switch to? 94
    Vumerity
79 (84.0%)
    Bafiertam
15 (16.0%)
age_switch 93
    Mean (SD)
45.0 (10.1)
    Median (IQR)
44.0 (39.0 - 53.0)
    Range
22.0 - 67.0
    Missing
1
1 n (%)

2.5 ALC

Baseline lab is from the closest date prior to switch within 13 months

Follow-up is the lowest ALC value within 18 months after a switch

Characteristic Baseline, N = 881 Follow-up, N = 881
ALC value

    Mean (SD) 1.6 (0.7) 1.3 (0.8)
    Median (IQR) 1.5 (1.2 - 1.9) 1.1 (0.7 - 1.6)
    Range 0.4 - 4.0 0.3 - 4.8
ALC grade

    [0.27,0.50) 1 (1.14%) 9 (10.2%)
    [0.50,0.80) 3 (3.41%) 21 (23.9%)
    [0.80,1.00) 8 (9.09%) 9 (10.2%)
    [1.00,4.80] 76 (86.4%) 49 (55.7%)
Months from switch

    Mean (SD) -3.4 (3.3) 9.8 (4.5)
    Median (IQR) -2.5 (-5.1 - -0.6) 10.2 (6.4 - 13.3)
    Range -12.6 - 0.0 0.2 - 17.7
Percent change

    Mean (SD) 0.0 (0.0) -20.4 (41.2)
    Median (IQR) 0.0 (0.0 - 0.0) -21.0 (-44.0 - -4.8)
    Range 0.0 - 0.0 -80.5 - 241.8
Categorical percent change

    [-80.5,-50.0) 0 (0%) 17 (19.3%)
    [-50.0,-40.0) 0 (0%) 7 (7.95%)
    [-40.0,-30.0) 0 (0%) 9 (10.2%)
    [-30.0,-20.0) 0 (0%) 12 (13.6%)
    [-20.0,-10.0) 0 (0%) 14 (15.9%)
    [-10.0, 0.0) 0 (0%) 12 (13.6%)
    [ 0.0,241.8] 88 (100.0%) 17 (19.3%)
1 n (%)

Characteristic N Baseline, N = 88 Follow-up, N = 88 p-value1
ALC value 176

<0.001
    Mean (SD)
1.61 (0.66) 1.27 (0.78)
    Median (IQR)
1.46 (1.20 - 1.92) 1.11 (0.66 - 1.58)
    Range
0.40 - 4.04 0.27 - 4.80
1 Wilcoxon signed rank test with continuity correction
Characteristic N N = 88
difference 88
    Mean (SD)
-0.35 (0.57)
    Median (IQR)
-0.34 (-0.53 - -0.07)
    Range
-2.56 - 0.97
Characteristic Baseline Bafiertam, N = 131 Baseline Vumerity, N = 751 Follow-up Bafiertam, N = 131 Follow-up Vumerity, N = 751
ALC value



    Mean (SD) 2.0 (0.8) 1.5 (0.6) 2.1 (1.0) 1.1 (0.7)
    Median (IQR) 2.0 (1.4 - 2.4) 1.4 (1.1 - 1.8) 2.0 (1.4 - 2.4) 1.0 (0.6 - 1.4)
    Range 0.8 - 4.0 0.4 - 3.7 1.1 - 4.8 0.3 - 3.3
ALC grade



    [0.27,0.50) 0 (0%) 1 (1.33%) 0 (0%) 9 (12.0%)
    [0.50,0.80) 0 (0%) 3 (4.00%) 0 (0%) 21 (28.0%)
    [0.80,1.00) 1 (7.69%) 7 (9.33%) 0 (0%) 9 (12.0%)
    [1.00,4.80] 12 (92.3%) 64 (85.3%) 13 (100.0%) 36 (48.0%)
Months from switch



    Mean (SD) -3.2 (3.2) -3.4 (3.3) 9.6 (4.8) 9.9 (4.4)
    Median (IQR) -1.6 (-5.4 - -1.1) -2.9 (-5.1 - -0.6) 8.2 (6.0 - 11.8) 10.3 (6.6 - 13.3)
    Range -9.6 - 0.0 -12.6 - 0.0 3.3 - 17.7 0.2 - 17.3
Percent change



    Mean (SD) 0.0 (0.0) 0.0 (0.0) 4.3 (20.0) -24.7 (42.5)
    Median (IQR) 0.0 (0.0 - 0.0) 0.0 (0.0 - 0.0) 5.9 (-12.9 - 15.5) -25.9 (-47.0 - -9.6)
    Range 0.0 - 0.0 0.0 - 0.0 -23.4 - 50.6 -80.5 - 241.8
Categorical percent change



    [-80.5,-50.0) 0 (0%) 0 (0%) 0 (0%) 17 (22.7%)
    [-50.0,-40.0) 0 (0%) 0 (0%) 0 (0%) 7 (9.33%)
    [-40.0,-30.0) 0 (0%) 0 (0%) 0 (0%) 9 (12.0%)
    [-30.0,-20.0) 0 (0%) 0 (0%) 1 (7.69%) 11 (14.7%)
    [-20.0,-10.0) 0 (0%) 0 (0%) 3 (23.1%) 11 (14.7%)
    [-10.0, 0.0) 0 (0%) 0 (0%) 2 (15.4%) 10 (13.3%)
    [ 0.0,241.8] 13 (100.0%) 75 (100.0%) 7 (53.8%) 10 (13.3%)
1 n (%)

2.6 Transfer assessments

Characteristic N Instance Overall, N = 201
1, N = 171 2, N = 31
Medication Name 20


    Tecfidera
9 (52.9%) 1 (33.3%) 10 (50.0%)
    Vumerity
5 (29.4%) 0 (0%) 5 (25.0%)
    Bafiertam
3 (17.6%) 2 (66.7%) 5 (25.0%)
Why did the patient switch pharmacies? 20


    Insurance change/mandate
12 (70.6%) 2 (66.7%) 14 (70.0%)
    PAP supplies medications
4 (23.5%) 0 (0%) 4 (20.0%)
    Patient preference
0 (0%) 1 (33.3%) 1 (5.00%)
    VSP fill limit reached
1 (5.88%) 0 (0%) 1 (5.00%)
Where is the patient filling now? 20


    Accredo
3 (17.6%) 1 (33.3%) 4 (20.0%)
    CVS Specialty
3 (17.6%) 1 (33.3%) 4 (20.0%)
    PAP
4 (23.5%) 0 (0%) 4 (20.0%)
    Walgreens Specialty Pharmacy
3 (17.6%) 0 (0%) 3 (15.0%)
    OptumRx/Briova
2 (11.8%) 0 (0%) 2 (10.0%)
    Cigna
1 (5.88%) 0 (0%) 1 (5.00%)
    IngenioRx
1 (5.88%) 0 (0%) 1 (5.00%)
    Null
0 (0%) 1 (33.3%) 1 (5.00%)
1 n (%)

2.7 Discontinuation assessments

Characteristic N Instance Overall, N = 881
1, N = 861 2, N = 21
Medication that was discontinued 86


    Tecfidera
57 (67.9%) 0 (0%) 57 (66.3%)
    Dimethyl fumarate
25 (29.8%) 1 (50.0%) 26 (30.2%)
    Vumerity
2 (2.38%) 1 (50.0%) 3 (3.49%)
    Missing
2 0 2
Why did the patient discontinue therapy? 86


    Financial limitations/changes
43 (51.2%) 0 (0%) 43 (50.0%)
    Insurance change/mandate
25 (29.8%) 0 (0%) 25 (29.1%)
    Common side effects
14 (16.7%) 2 (100.0%) 16 (18.6%)
    Major side effects/complications
1 (1.19%) 0 (0%) 1 (1.16%)
    Noncompliance
1 (1.19%) 0 (0%) 1 (1.16%)
    Missing
2 0 2
What therapy was started? 86


    Vumerity
70 (83.3%) 1 (50.0%) 71 (82.6%)
    Bafiertam
14 (16.7%) 1 (50.0%) 15 (17.4%)
    Missing
2 0 2
1 n (%)

2.7.1 Reason for switch (including med switched to)

2.7.2 Reason for switch

3 Analysis

Characteristic N DRF, N = 751 MMF, N = 131 Overall, N = 881
Sex 88


    Female
58 (77.3%) 12 (92.3%) 70 (79.5%)
    Male
17 (22.7%) 1 (7.69%) 18 (20.5%)
Race 88


    White
58 (77.3%) 9 (69.2%) 67 (76.1%)
    Black or African American
13 (17.3%) 2 (15.4%) 15 (17.0%)
    American Indian or Alaska Native
1 (1.33%) 0 (0%) 1 (1.14%)
    Decline to Answer
2 (2.67%) 1 (7.69%) 3 (3.41%)
    Unknown
1 (1.33%) 1 (7.69%) 2 (2.27%)
BMI 86


    Mean (SD)
29.7 (5.9) 26.9 (6.2) 29.3 (6.0)
    Median (IQR)
29.4 (25.6 - 33.4) 25.2 (22.4 - 32.0) 29.0 (25.4 - 33.4)
    Range
17.5 - 50.5 18.5 - 36.7 17.5 - 50.5
    Missing
1 1 2
ALC percent change from baseline 88


    Mean (SD)
-24.7 (42.5) 4.3 (20.0) -20.4 (41.2)
    Median (IQR)
-25.9 (-47.0 - -9.6) 5.9 (-12.9 - 15.5) -21.0 (-44.0 - -4.8)
    Range
-80.5 - 241.8 -23.4 - 50.6 -80.5 - 241.8
age_switch 88


    Mean (SD)
44.8 (10.6) 44.2 (8.3) 44.8 (10.2)
    Median (IQR)
44.0 (38.5 - 52.5) 44.0 (40.0 - 51.0) 44.0 (38.8 - 52.3)
    Range
22.0 - 67.0 32.0 - 57.0 22.0 - 67.0
Was there a gap between Tecfidera and switching to the other fumarate? 85


    No
63 (87.5%) 12 (92.3%) 75 (88.2%)
    Yes
9 (12.5%) 1 (7.69%) 10 (11.8%)
    Missing
3 0 3
Time taking Tecfidera before switching to Vumerity or Baferitam (months) 88


    Mean (SD)
46.0 (31.6) 62.4 (34.3) 48.4 (32.4)
    Median (IQR)
41.2 (17.5 - 74.0) 70.1 (48.2 - 93.4) 47.2 (19.5 - 76.1)
    Range
1.6 - 113.6 1.1 - 103.1 1.1 - 113.6
Number of previous DMTs 88


    0
30 (40.0%) 4 (30.8%) 34 (38.6%)
    1
26 (34.7%) 5 (38.5%) 31 (35.2%)
    2
13 (17.3%) 3 (23.1%) 16 (18.2%)
    3
3 (4.00%) 0 (0%) 3 (3.41%)
    4
3 (4.00%) 0 (0%) 3 (3.41%)
    5
0 (0%) 1 (7.69%) 1 (1.14%)
1 n (%)

Linear Regression Model

ols(formula = pct.change ~ sex + n_prev_dmts + age_switch + time_switch + 
    second_fum2 + bmi, data = ms)
Frequencies of Missing Values Due to Each Variable
 pct.change         sex n_prev_dmts  age_switch time_switch second_fum2 
          6           0           0           1           0           0 
        bmi 
          2
Model Likelihood
Ratio Test		 Discrimination
Indexes
Obs 86 LR χ2 9.98 R2 0.110
σ 40.5867 d.f. 6 R2adj 0.042
d.f. 79 Pr(>χ2) 0.1256 g 14.801

Residuals

    Min      1Q  Median      3Q     Max 
-63.426 -17.437  -1.811  12.630 258.642
β S.E. t Pr(>|t|)
Intercept  -14.1352  31.8366 -0.44 0.6583
sex=Male  -18.1499  10.9142 -1.66 0.1003
n_prev_dmts   -3.6123   4.2968 -0.84 0.4031
age_switch   -0.0906   0.4715 -0.19 0.8481
time_switch   -0.0452   0.1498 -0.30 0.7636
second_fum2=MMF   30.1102  13.3102 2.26 0.0264
bmi   0.1227   0.7568 0.16 0.8716
label levels effect conf.low conf.high d.f. P
Sex Male vs. Female -18.150 -39.874 3.574 1 0.100
Number of previous DMTs 1 vs. 0 -3.612 -12.165 4.940 1 0.403
Age at switch 55 vs. 40 -1.359 -15.437 12.718 1 0.848
Time to switch 60 vs. 30 -1.357 -10.303 7.590 1 0.764
BMI 30 vs. 25 0.614 -6.918 8.145 1 0.872
Medication switched to MMF vs. DRF 30.110 3.617 56.603 1 0.026