Guidelines written by Dr. Ben Turner, Professor Gavin Giovannoni, Dr. Klaus Schmierer October 2014 Review October 2016

Barts-MS Clinical Guidance #1-2014

Original guidance published: This is new guidance

Management of lymphopaenia in people with multiple sclerosis treated with Dimethyl Fumarate or DMF (Tecfidera)

BACKGROUND As stated in the EMA’s Summary of Product Characteristics (SmPC), dimethyl fumarate (Tecfidera) may decrease lymphocyte counts (1). Lymphopenia and leucopenia are listed as common undesirable effects associated with DMF use (≥1/100 to <1/10) (1). In the phase III placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with DMF, mean lymphocyte counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits (1). In phase III studies, lymphocyte counts <0.5x109/l were observed in <1% of patients treated with placebo and 6% of patients treated with DMF (1, 5). A lymphocyte count <0.2x109/l was observed in 1 patient treated with DMF and in no patients treated with placebo (1-7). Across phase IIb and III studies, an increased incidence of infections and serious infections was not observed in patients with lymphocyte counts <0.8x109/l or <0.5x109/l. (1-7). Although there is no advice within the SmPC regarding cessation of therapy following lymphocyte count reductions (1), in view of the recent fatal case of PML in a patient treated with DMF for over 4-years, who had a persistent lymphopaenia below <0.5x109/l this advice will almost certainly be changed. We therefore feel it is appropriate to make the following recommendations. The SmPC currently states that prior to initiating treatment with DMF, a recent complete blood count (i.e. within 6 months) should be available. Assessments of complete blood counts are also recommended after 6 months of treatment and every 6 to 12 months thereafter and as clinically indicated (1). As there are no specific recommendations for the management of reduced lymphocyte counts in patients receiving DMF the management is therefore at the clinical discretion of the prescribing neurologists. Tecfidera Summary of Product Characteristics (SmPC) As stated in the SmPC, Tecfidera may decrease lymphocyte counts (1). Lymphopenia and leucopenia are listed as common undesirable effects associated with Tecfidera use (≥1/100 to <1/10) (1). Tecfidera has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised when treating these patients (1). In the placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with Tecfidera, mean lymphocyte counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts <0.5x109/l were observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte count <0.2x109/l was observed in 1 patient treated with Tecfidera and in no patients treated with placebo (1). The incidence of infections (58% versus 60%) and serious infections (2% versus 2%) was similar in patients treated with placebo or Tecfidera. An increased incidence of infections and serious infections was not observed in patients with lymphocyte counts <0.8x109/l or <0.5x109/l. A transient increase in mean eosinophil counts was seen during

Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital, The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital. Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014. Scheduled review October 2016

the first 2 months of therapy (1). There is no advice within the SmPC regarding cessation of therapy following lymphocyte count reductions (1). However of note, it is advised that if a patient develops a serious infection, suspending treatment with Tecfidera should be considered and the benefits and risks should be reassessed prior to re-initiation of therapy. Patients with serious infections should not start treatment with Tecfidera until the infection(s) is resolved (1). Prior to initiating treatment with Tecfidera, a recent complete blood count (i.e. within 6 months) should be available. Assessments of complete blood counts are also recommended after 6 months of treatment and every 6 to 12 months thereafter and as clinically indicated (1). Pivotal Phase III Clinical Trials of Tecfidera in RRMS DEFINE STUDY The DEFINE (Determination of the Efficacy and Safety of Oral Fumarate In Relapsing-Remitting Multiple Sclerosis) study was a global, randomised, double-blind, placebo-controlled, 2-year Phase III study evaluating the efficacy and safety of oral Tecfidera (240 mg) administered either 2 times daily (BID) or 3 times daily (TID) in patients with RRMS (2). Haematology laboratory parameters were assessed at baseline, every 4 weeks for the first 12 weeks, and every 12 weeks thereafter (3). A total of 1234 patients were enrolled and received at least one dose of the study drug (n = 408 in the placebo arm, n = 410 in the BID arm, and n = 416 in the TID arm) (2). Mean white blood cell (WBC) and lymphocyte counts in both Tecfidera groups decreased over the first year and then plateaued, with mean values remaining within normal limits. Mean WBC and lymphocyte counts decreased by approximately 10% and 28%, respectively at 1 year (2). WBC counts of less than 3.0 x109/L or lymphocyte counts of less than 0.5 x 109/L (corresponding to the National Cancer Institute Common Toxicity Criteria grade 3 or higher lymphopenia and grade 2 or higher leukopenia, respectively) were seen in 4% of Tecfidera patients, versus 1% or less of placebo patients. There were no serious infections in patients with lymphocyte counts <0.5x109/L. No patient stopped treatment due to low or decreased WBC or lymphocyte counts (3). CONFIRM STUDY CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis) was a global, randomised, double-blind, placebo-controlled, 2-year Phase III study evaluating the efficacy and safety of oral Tecfidera (240 mg) administered either BID or TID in patients with RRMS (4). The study also had an open-label comparator arm with glatiramer acetate (GA). Haematology laboratory parameters were assessed at baseline, every 4 weeks for 12 weeks, and every 12 weeks thereafter (5). A total of 1430 patients were randomised, and 1417 patients were included in the safety population (n = 363 subjects in the placebo arm, n = 359 in the Tecfidera BID arm, n = 344 in the TID arm, n = 351 in the GA arm) (4). Similar to DEFINE, mean WBC and lymphocyte counts in both Tecfidera groups decreased during the first year and then plateaued; mean values throughout the study remained within normal limits (4,5). At 1 year of treatment, mean WBC counts and lymphocyte counts in the Tecfidera groups decreased by approximately 11% to 12% and 28% to 32%, respectively, relative to baseline (4). WBC counts of less than 3.0x109/L and lymphocyte counts of less than 0.5 x109/L (corresponding to the National Cancer Institute Common Toxicity Criteria grade 2 or higher lymphopenia and grade 3 or higher

Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital, The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital. Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014. Scheduled review October 2016

leukopenia, respectively) were seen in 7-10% and 4-5%, respectively in the BID and TID Tecfidera groups, versus 1% or less of the patients in the placebo group (4). One patient stopped treatment due to low or decreased WBC count. No patient stopped treatment due to low or decreased lymphocyte count. There were no serious infections reported in patients with lymphocyte counts < 0.5 x 109/L (6). Integrated Analysis of Tecfidera Phase IIb and III Studies An integrated analysis of the phase IIb and III studies was conducted to describe the clinical relevance of lymphocyte count reductions in patients treated with Tecfidera 240 mg BID or TID (7). A total of 2,428 RRMS patients were randomized and received treatment with placebo (n=836), Tecfidera BID (n=769), or Tecfidera TID (n=823). In these studies there was no stopping rule based on low lymphocyte counts. However there were stopping rules for low WBC counts. Study treatment had to be discontinued in patients with low WBC counts per the following rules:

• Phase IIb: WBC <1.5x109/L at any time during the study or WBC counts <2.0x109/L sustained for 4 weeks

• Phase III - DEFINE and CONFIRM: WBC count <2.0x109/L sustained for 4 consecutive weeks after study treatment was withheld; or a WBC count <2.0x109/L confirmed on re-testing

In Tecfidera-treated patients, mean WBC and lymphocyte counts decreased from baseline by approximately 11% and 30%, respectively, through week 48, then plateaued, but remained within normal limits throughout the observation period. There was an increased incidence of lymphopenia categorised as CTC Grades 1, 2, or 3 in Tecfidera-treated patients relative to placebo. The percentages of patients with at least one, more than one and consecutive Grade 3 or 4 lymphocyte counts were increased among Tecfidera treated patients relative to placebo. The incidence of ≥1 Grade 3 or 4 lymphocyte count was 6% for the Tecfidera BID group versus <1% for placebo. The incidence of CTC Grade 3 or 4 lymphopenia increased over time through Week 48, then stabilised (7). An increased incidence of infections and serious infections was not observed in patients with lymphocyte counts <0.8x109/l or <0.5x109/L. No serious infections were reported in any Tecfidera-treated patient with a minimum post-baseline lymphocyte count <0.5 x 109/L (7). Across the studies, one patient in the Tecfidera TID group discontinued study drug due to an adverse event associated with leukopenia. No Tecfidera-treated patients discontinued study drug due to lymphopenia (7). Extension study of Pivotal Clinical Trials of Tecfidera in Multiple Sclerosis (ENDORSE) ENDORSE is an ongoing multicentre, parallel-group, dose-blinded study with up to 5 or more years of follow up. Eligible patients who completed the 2-year parent studies (DEFINE and CONFIRM) were enrolled. Patients who received Tecfidera 240 mg BID or TID for up to 2 years in the parent study remained on the same Tecfidera dose in ENDORSE. Patients who received placebo (both parent studies) or GA (CONFIRM) were randomised 1:1 to Tecfidera 240 mg BID or TID. Haematology laboratory parameters were assessed at baseline and every 12 weeks thereafter. (8). In an interim analysis (database lock June 2013), patients continuing on Tecfidera in ENDORSE maintained stable WBC and lymphocyte counts. Patients new to Tecfidera in ENDORSE had WBC and lymphocyte counts similar to those seen in the parent studies. WBC counts were < 3.0 x 109/L in 6-7%

Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital, The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital. Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014. Scheduled review October 2016

of patients in the continued Tecfidera groups and in 7-10% of patients in the new to Tecfidera groups. Lymphocyte counts were < 0.5 x 109/L in 6-8% of patients in the continued Tecfidera groups and in 5-9% of patients in the new to Tecfidera groups (8). BARTS HEALTH ADVICE Patients starting DMF should be counselled that there has been one fatal case of PML in a patient with MS taking DMF for over 4 years, who had a persistent lymphopaenia of less than < 0.5 x 109/L, and one patient with psoriasis who developed PML on a propriety formulation of DMF who also had persistent lymphopaenia (). We believe the risk of PML in patients with a lymphocyte count above 0.8 x 109/L is very low. At present we have no evidence that PML risk is due to a specific action of DMF other than its impact on total lymphocyte counts. PROTOCOL

1. Before starting DMF an up-to-date (within the last 4 weeks) full blood count (FBC) is required in addition lymphocyte subset; collecting data on lymphocyte is to allow the profiling of the immunological effects of DMF in more detail.

2. The monitoring of FBC with lymphocyte counts and subsets should be done at 3 months and 6 months, and then at 6 monthly intervals in patients with lymphocyte counts above 1.2 x 109/L. In patients with total lymphocyte counts less than 1.2 x 109/L monitoring should be done at 3 monthly intervals.

3. If the lymphocyte counts return to above 1.2 x 109/L, then 6 monthly monitoring should be reinstated.

4. If the total lymphocyte count falls below 0.8 x 109/L, and is confirmed on a second FBC and the patient wants to stay on DMF it may be worth checking the JCV virus status. As DMF-related lymphopaenia is a form of immunosuppression the JCV index, as measured using the STRATIFY JCV assay, cannot be used to assess PML risk (11). Please note a lymphocyte count cut-off of 0.8 x 109/L (WHO grade 2) may considered by some as being too conservative; but until data emerges to show that DMF-related lymphopaenia is reversible we feel this conservative approach is justified.

5. If lymphocytes remain persistently below 0.8 x 109/L, consider the risks and benefits of continuing DMF.

6. If lymphocytes go below 0.5 x 109/L we recommend stopping DMF. 7. At present we are not aware of any data to indicate that reducing the dose of DMF will

result in the lymphocyte counts recovering. In addition, a lower dose than 240mg BD of DMF is unlikely to be effective (10).

8. All patients treated with DMF should have annual Gd-enhanced MRI studies according to our Barts MS MRI protocol, and additional MRI studies if clinically indicated.

ADDITIONAL COMMENTS We define significant immunosuppression on DMF as persistent lymphopaenia for greater than 6 months with a total lymphocyte count of less than 1.2 x 109/L (WHO Grade 1). In patients with a past history of significant immunosuppression the JCV serology index, as measured using the STRATIFY JCV assay, cannot be used to complement PML risk profiling (11).

Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital, The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital. Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014. Scheduled review October 2016

REFERENCES

1. Tecfidera Summary of Product Characteristics, January 2014. Available from www.medicines.org.uk [Accessed 19 March 2014]

2. Gold R, Kappos L, Arnold DL, et al.Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. N Engl J Med. 2012;367(12):1098-107.

3. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098-107.

4. Fox RJ, Miller DH, Phillips JT, et al. Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis. N Engl J Med. 2012;367(12):1087-97.

5. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087-97.

6. Phillips JT. Fox RJ, Kita M, et al. Safety and Tolerability of BG-12 in the Phase 3 CONFIRM Study. Fourth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, May 30–June 2, 2012; San Diego, CA, USA.

7. Phillips JT,Fox RJ,Selmaj K, Zhang R, Novas M, Sweetser MT, Viglietta V, Gold R. Safety Profile of BG-12 (Dimethyl Fumarate) in Relapsing-Remitting Multiple Sclerosis: Long-term Interim Results From the ENDORSE Extension Study. Presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis 2–5 October 2013 Copenhagen, Denmark. P 996.

8. Fox RJ,1 Gold R,2 Phillips JT, ET AL. Lymphocyte Count Reductions in Relapsing- Remitting Multiple Sclerosis (RRMS) Patients Treated With Oral BG-12 (dimethyl fumarate): Integrated Analysis of the Placebo-Controlled Studies. P1018. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 2−5 October, 2013, Copenhagen, Denmark.

9. European Public Assessment Report – Tecfidera. Assessment Report accessed at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-Public_assessment_report/human/002601/WC500162070.pdf [13 March 2014].

10. van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP. PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013 Apr 25;368(17):1658-9.

11. Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B,Campagnolo D, Belachew S, Ticho B. Anti-JCV antibody levels in serum or plasma further define risk of natalizumab-associated PML. Ann Neurol. 2014 Oct 1. doi: 10.1002/ana.24286. [Epub ahead of print] PubMed PMID: 25273271.