An Analysis of Monthly Surveillance 3T MRI in MS patients switched from long term natalizumab to teriflunomide in a controlled, prospective study

K. Edwards,1 S. Cohan,2 J Thomas3

1MS Center of Northeastern New York (Latham, NY, USA), 2 Providence Multiple Sclerosis Center (Portland, OR, USA), 3 Albany Medical College (Albany, NY, USA)

Objective

Background

Methods

1. Petty M, Lee L, Ying X, et al. Teriflunomide treatment reduces infiltration of macrophages, T cells and B cells, and increases survival of oligodendrocytes in the spinal cord of the Dark Agouti rat model of experimental allergic encephalomyelitis. Neurology 2010;74:Suppl2:A415. abstract

2. Miravalle A, Jensen R, Kinkel RP. Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol 2011; 68:186-91.

3. Havla J, Tackenberg B, Hellwig K, et al. Fingolimod reduces the risk of recurrence of disease activity during the first 12 months after natalizumab discontinuation in multiple sclerosis. P536. Multiple Sclerosis Journal 2012; 18: (S4) 230

4. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med 2011;365:1293-303.

5. Confavreux C, O'Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014;13:247-56

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Natalizumab (NTZ) has the risk of causing progressive multifocal leukoencephalopathy (PML) in patients after extended use and with detectable anti-JCV-antibodies. . There is a need for alternative disease modifying treatment (DMT) that would be safe and effective to prevent recurrence of MS exacerbations upon discontinuation of NTZ.

Patients with relapsing forms of multiple sclerosis (MS) must have received 12 or more NTZ treatments and be anti-JCV-ab positive and not have had prior immunosuppressive therapy. Patients had to be free of clinical relapses during prior 12 months of NTZ treatment. Patients began 14 mg teriflunomide within 4 weeks after last dose of NTZ. Monthly 3T brain MRI, EDSS, laboratory tests, interim history and physical examination were done for 6 months and compared to each patient’s baseline values.

There is a need for a DMT for patients with RMS who should discontinue NTZ due to risk of PML. Little evidence of disease activity was seen during the first 6 months after switching, precisely the time when high relapse rates have been following discontinuation of NTZ, further supporting a role for teriflunomide in the treatment of patients discontinuing NTZ. Teriflunomide may be a potential therapy after NTZ. It is important to switch to teriflunomide from natalizumab as soon as practical.  The initiation of teriflunomide within the first 4 weeks from the last natalizumab dose proved safe and effective.  This is likely a crucial factor in the patient stabilization and protection from natalizumab withdrawal in this population.

To explore the safety and efficacy of teriflunomide in patients switching from NTZ to teriflunomide .

Conclusions

The data below is a 6 month interim analysis of an on-going study. There were 15 patients enrolled. Mean age was 48. Eighty seven percent were female. The mean EDSS at baseline was 3.43; at 6 months was 3.17. The mean number of NTZ treatments prior to treatment with teriflunomide was 52.

MRI results showed 13 of the 15 patients stable in all parameters from baseline to month 6. No patients had new or enlarging T2 hyperintensities. Contrast enhancing lesions occurred in two patients. One patient had a 5 mm pericallosal lesion at month 3 without symptoms which resolved on month 4 MRI. Another patient had two 3 mm lesions in the pons at six months without symptoms. Leg weakness did occur 2 weeks later which resolved after IV steroids. Teriflunomide was continued in all patients. There was no emergence of PML.

Results

References

Patients switched from natalizumab to teriflunomide, n=15

Percentage Mean (SD) Range

Female (n=13) 87% n/a n/a

Age (n=15) n/a 48 (6.4) 40-57

Total No of years of MS n/a 15 (5.49) 2.3-21.24

Baseline EDSS n/a 3.43 (1.29) 2-6

EDSS at month 6 n/a 3.17 (1.4) 1.5 - 6

Number of natalizumab infusions (SD) n/a 52 (21.97) 12-94

Number of months on natalizumab (SD) n/a 49 (21.5) 12 - 86

Table 1: Patient demographics

Supported by an unrestricted educational grant from Genzyme, A Sanofi Company

# Patient # Age Gender Baseline EDSS # of Exacerbations 1 year prior to NAT

start

# of GAD Enhancing Lesions on MRI 1 year

prior to NAT start

1. 101 44 Female 3.0 2 02. 102 42 Female 3.5 2 03. 103 42 Male 2.0 2 14. 104 57 Female 6.0 3 0

5. 105. 40 Female 4.5 1 0

6. 106. 42 Female 3.0 2 37. 107. 54 Female 6.0 2 48. 108. 43 Female 3.5 3 09. 109. 49 Female 2.0 1 0

10. 110. 57 Male 2.0 4 0

11. 111. 52 Female 4.0 5 1

12. 113. 57 Female 4.0 0 0

13. 114. 40 Female 2.5 2 1

14. 115. 48 Female 3.0 2 0

15. 117. 51 Female 2.5 0 0

Mean 48 3.43

Table 2: Baseline data

# Patient #

Age Gender EDSS at Month 6

EDSS Status # of New GAD Enhancing Lesions on

MRI while on Teriflunomide

Lesions occurring at

Month #

Relapse

1. 101 44 Female 2.5 Improved by 0.5 0 - No2. 102 42 Female 2.5 Improved by 1.0 0 - No3. 103 42 Male 2.0 No change 2 Month 6 Yes4. 104 57 Female 6.0 No change 0 Month 6 Yes

5. 105. 40 Female 4.5 No change 0 - No

6. 106. 42 Female 3.0 No change 0 - No7. 107. 54 Female 6.0 No change 0 - No8. 108. 43 Female 2.5 Improved by 1.0 1 Months 3,4 No9. 109. 49 Female 1.5 Improved by 0.5 0 - No

10. 110. 57 Male 2.0 No change 0 - No11. 111. 52 Female 2.5 Improved by 1.5 0 - No12. 113. 57 Female 3.5 Improved by 0.5 0 - No13. 114. 40 Female 3.0 Worse by 0.5 0 - No14. 115. 48 Female 4.0 Worse by 1.0 0 - No15. 117. 51 Female 2.0 Improved by 0.5 0 - No

Mean 48 3.17

Table 3: Data at 6 months on Teriflunomide

No patients discontinued Teriflunomide after 6 months

DISCLOSURES: KE: Received funding as consultant/advisor/speaker for Biogen, Genzyme, Novartis and research support from Actelion, Biogen, Eli Lilly, Eisai, Genentech, Genzyme, Novartis, TauRx Therapeutics, Vaccinex; SC: Received funding as consultant/advisor/speaker for Acorda, Biogen Idec, Sanofi & Novartis and research support from Biogen Idec & Sanofi. JT: None