Safety, Tolerability, and Pharmacokinetics of BG-12 Administered with and without Aspirin:

Key Findings from a Randomized, Double-blind, Placebo-controlled Trial in Healthy Volunteers

Sheikh SI,1 Nestorov I,1 Russell H,2 O’Gorman J,1 Huang R,1 Milne GL,3 Stecher S,1 Novas M,1 Dawson KT1
1
Biogen Idec Inc., Weston, MA, USA; 2PROMETRIKA, LLC, Cambridge, MA, USA; 3Vanderbilt University, Nashville, TN, USA P04.136

Subject-reported Flushing Outcomes

INTRODUCTION RESULTS •  GFSS and FSS scores were low in all groups, with mean scores less than 4. Figure 3: Median plasma concentrations of 9α,11β-PGF2 during the
–– Mean GFSS and FSS scores were lower in subjects treated with aspirin than in study: a) Day 1 and b) Day 4
•  BG-12 (dimethyl fumarate) and its primary metabolite, monomethylfumarate •  All enrolled subjects received the study drug and completed the study. those who were not (Figure 2).
(MMF), have been shown to activate the nuclear factor (erythroid-derived 2)-like 2 Placebo (n=6) BG-12 BID (n=6) BG-12 TID (n=6)
(Nrf2) transcriptional pathway. Experimental evidence suggests that BG-12 may PK Profiles
provide anti-inflammatory and potential neuroprotective effects.1 •  There was no evidence of accumulation of MMF during the study, based on   Figure 2: Mean flushing severity scores over time: a) GFSS and b) FSS a) Day 1
BG-12 alone BG-12 with aspirin
pre-dose plasma MMF levels on Day 4 and further evidenced by stability of the PK 0.06 0.06

9α,11β-PGF2 (ng/mL)
•  Two Phase 3 studies in patients with relapsing–remitting multiple sclerosis (MS)
parameters throughout the study. 0.05 0.05

Median plasma
treated with oral BG-12, DEFINE and CONFIRM, have shown improvements in Placebo (n=6) BG-12 BID (n=6) BG-12 TID (n=6)
clinical and neuroradiologic measures of MS disease activity, including significant –– Although inter-subject variability was high, median values for PK parameters 0.04 0.04
were similar with and without aspirin on Day 1 and Day 4, for each BG-12 a) GFSS BG-12 alone BG-12 with aspirin
reductions in relapse rates and brain lesion activity on magnetic resonance 0.03 0.03
10 10
imaging.2–5 regimen (Table 1). 0.02 0.02

Mean GFSS score

5 5 0.01
•  AUC0–10h values were generally dose-proportional and t1/2 values were very short. 0.01
•  In studies to date, common adverse events (AEs) reported by subjects receiving BG-12 4 4
–– tmax values were consistently higher for TID dosing, compared with BID dosing, 0 0
include flushing and gastrointestinal (GI) disturbances typically reported as mild-to- 3 3 0 2 4 6 8 10 12 0 2 4 6 8 10 12
moderate in severity, with the incidence decreasing after the first month of treatment. as expected due to carry over of exposure from the first dose at the time of the
Time (hours) Time (hours)
second dose. 2 2
1 1 b) Day 4
•  Aspirin pre-treatment did not significantly affect MMF concentration–time profiles BG-12 alone BG-12 with aspirin
following administration of BG-12 (Figure 1). 0 0 0.06 0.06

9α,11β-PGF2 (ng/mL)
1 2 3 4 5 1 2 3 4 5 0.05 0.05

Median plasma
Time (days) Time (days)
OBJECTIVES b) FSS
0.04 0.04
0.03 0.03
BG-12 alone BG-12 with aspirin
Table 1: Median pharmacokinetic parameters of BG-12 with and  

Mean overall FSS score

•  To investigate the safety, tolerability, and pharmacokinetic (PK) profiles of BG-12 10 10 0.02 0.02
administered with and without aspirin during 4 days of dosing. without aspirin 5 5 0.01 0.01
4 4 0 0
•  To evaluate potential mediators of BG-12-induced flushing. 0 2 4 6 8 10 12 0 2 4 6 8 10 12
BG-12 BID BG-12 TID 3 3
Time (hours) Time (hours)
Parameter Without aspirin With aspirin Without aspirin With aspirin 2 2
Lower limit of quantification = 0.001 ng/mL.
1 1
n 6 6 6 6
0 0
METHODS AUC0–10 (h·ng/mL) 0 4 8 12 0 4 8 12 0 4 8 12 0 4 8 12 0
Day 1 Day 2 Day 3 Day 4 Day 5
0 4 8 12 0 4 8 12 0 4 8 12 0 4 8 12 0
Day 1 Day 2 Day 3 Day 4 Day 5
•  No remarkable abnormalities in vital signs, ECGs or laboratory values were noted
during the study. No subjects withdrew and there were no serious AEs or deaths
Day 1 2,800 3,020 5,075 5,875
Time (hours) Time (hours) during the study.
Subjects Day 4 2,865 2,590 5,815 5,885
•  Healthy volunteers aged 18–55 years were recruited to the study.
•  Subjects with a history of GI disturbances, or who had used non-steroidal anti-
Cmax (ng/mL)
•  In all treatment groups, mean flushing severity was rated highest on Day 2 on
CONCLUSIONS
Day 1 1,335 1,625 1,935 1,970
inflammatory drugs or over-the-counter cold, allergy or GI medications within   Day 4 1,730 1,135 2,050 1,995 the GFSS (which measures flushing symptoms in the past 24 hours; i.e. Day 2
scores reported flushing from the first day of dosing), and Day 1 on the FSS (which •  There was no accumulation of MMF during 4 days of dosing with BG-12 
14 days prior to study Day 1 were excluded from the study.
tmax (hours) measures acute flushing symptoms). 240 mg BID or TID.
Study Design and Treatment Day 1 4.0 2.8 6.0 5.0 •  The safety and PK profiles of BG-12 evaluated over 4 days of dosing were not
•  Regardless of treatment assignment, all GFSS scores decreased over time in a
•  Randomized, double-blind, placebo-controlled, study. Day 4 3.0 3.5 5.5 3.5 similar manner and had returned to baseline by Day 11. affected by aspirin co-administration.
•  Subjects were randomized into different dosing groups, which included the BG-12 t1/2 (hours) •  Mean subject-reported flushing scores on the GFSS and FSS were mild
dosages evaluated in pivotal Phase 3 studies (BG-12 240 mg twice daily [BID] and Subject-reported GI Outcomes across BG-12-treated groups and decreased over the study period,
Day 1 0.81 0.59 0.85 0.81
BG-12 240 mg three times daily [TID]) and placebo, administered with or without •  Mean OGISS and AGISS scores were low throughout the study, reflective of mild suggesting a degree of tolerance may have developed.
Day 4 0.63 0.56 1.05 0.88
aspirin for 4 days (6 groups of 6 subjects). symptoms, regardless of treatment assignment.
–– Aspirin 325 mg or matching placebo was administered 30 minutes before each Lag time (hours) •  Pre-treatment with aspirin, a known prostaglandin inhibitor, decreased
•  There were no apparent treatment- or dose-related differences in GI symptoms the incidence and severity of flushing whilst having no adverse effect on GI
dose of BG-12. Day 1 0.50 0.25 0.5 1.75
and aspirin did not appear to modify the intensity of symptoms on either scale. symptoms.
•  All treatments were administered with a standardized meal given immediately Day 4 0.25 0.25 1.0 1.00
after dosing. •  Elevated levels of the PGD2 metabolite 9a,11b-PGF2 were seen in some
Potential Flushing Mediators
subjects following BG-12 administration, suggesting that flushing may, to
Study Assessments •  Plasma concentrations of 9α,11β-PGF2, the major metabolite of PGD2, were some extent, be mediated by PGD2. No elevations of PGD2 metabolites were
•  The PK profile of BG-12 was assessed by measuring the primary metabolite, elevated at around 2–4 hours on Day 1 in some subjects treated with BG-12 alone. seen in subjects pre-treated with aspirin.
MMF, in the plasma of subjects over 10 hours on Days 1 and 4. The BG-12-mediated rise in 9α,11β-PGF2 was not seen in subjects treated with
Figure 1: Mean plasma MMF concentrations over time: a) BG-12   the cyclo-oxygenase inhibitor aspirin (Figure 3).
•  PK parameters including area under the concentration–time curve (AUC), –– By Day 4, no major elevations in this metabolite were apparent in subjects
maximum plasma concentration (Cmax), time to Cmax (tmax), half-life (t1/2) and lag BID alone or with aspirin and b) BG-12 TID alone or with aspirin
treated with BG-12 either alone or with aspirin. REFERENCES
time were derived by non-compartmental analysis.
•  The urinary metabolite prostaglandin D-M (PGD-M) was elevated from baseline 1.  Linker RA, Lee DH, Ryan S, et al. Brain 2011;134:678–692.
•  Flushing severity was assessed by two validated subject-reported measures. BG-12 alone (n=6) BG-12 with aspirin (n=6) on Day 1 in some subjects treated with BG-12 alone; no elevations were seen in
–– The Global Flushing Severity Scale (GFSS)6,7 was administered prior to the first 2.  Gold R, Kappos L, Bar-Or A, et al. Mult Scler 2011;17(Suppl. 10):S34.
a) BG-12 BID subjects treated with aspirin, and levels had returned to baseline by Day 4 in all 3.  Arnold D, Gold R, Bar-Or A, et al. Mult Scler 2011;17(Suppl. 10):S369–370.
dose on Days 1–4 and at a follow-up visit on Day 11, which measured flushing 2,000 2,000 subjects.
concentration (ng/mL)

symptoms in the previous 24 hours. Day 1 Day 4 4.  Fox R, Miller DJ, Phillips T, et al. Presented at: AAN; April 21–28, 2012, New Orleans, Louisiana,
Mean plasma MMF

1,750 1,750
–– The Flushing Severity Scale (FSS; adapted from the Flushing Symptom •  No elevations in histamine were noted in any group. USA. Abstract 3068 (oral presentation S01.003).
1,500 1,500
5.  Miller DJ, Fox R, Phillips T, et al. Presented at: AAN; April 21–28, 2012, New Orleans, Louisiana,
Questionnaire6) was administered at 30-minute to 1-hour intervals over   1,250 1,250
Safety and Tolerability USA. Abstract 3290 (oral presentation S11.001).
12 hours from the first dose on Days 1–4, to measure acute flushing symptoms. 1,000 1,000
750 750 6.  Norquist JM, Watson DJ, Yu Q, et al. Curr Med Res Opin 2007;23:1549–1560.
–– Both measures rated flushing severity on a scale of 0–10, where 0 = no flushing, •  The most common AE was flushing; the incidence was reduced in subjects treated
500 500 7.  Paolini JF, Mitchel YB, Reyes R, et al. Int J Clin Pract 2008;62:896–904.
1–3 = mild flushing, 4–6 = moderate flushing, 7–9 = severe flushing and   with aspirin.
250 250
10 = extreme flushing. 0 0
–– In groups not receiving aspirin, flushing was reported for 3/6, 5/6 and 6/6
•  GI symptoms were assessed by two subject-reported scales: the Overall GI Pre-dose 0 1 2 3 4 5 6 7 8 9 10 Pre-dose 0 1 2 3 4 5 6 7 8 9 10
Time (hours) Time (hours)
subjects treated with placebo, BG-12 BID and BG-12 TID, respectively. DISCLOSURES
Symptom Scale (OGISS) measuring GI symptoms in the previous 24 hours, and the –– In the aspirin pre-treatment groups, flushing was reported for 2/6, 3/6 and 4/6
Acute GI Symptom Scale (AGISS) measuring acute GI symptoms. b) BG-12 TID subjects, respectively. SIS, IN, JO’G, RH, SS, MN, KTD: employees of Biogen Idec.
2,000 2,000
–– Both the OGISS and AGISS are 0–10 scales where 0 = no GI symptoms,   •  The incidence and intensity of flushing diminished over time, with or without aspirin.
concentration (ng/mL)

Day 1 Day 4 GLM: consultant to Roche USA on eicosanoid metabolite method development. GLM’s laboratory
Mean plasma MMF

1,750 1,750
1–3 = mild symptoms, 4–6 = moderate symptoms, 7–9 = severe symptoms and 1,500 1,500
–– Most subjects had flushing events on the first 2 or 3 days of dosing but only a received compensation from Biogen Idec Inc. for costs associated with performing the prostaglandin D2
10 = extreme symptoms. few subjects reported flushing on Day 4. metabolite analyses for this study.
1,250 1,250
•  Plasma and urine concentrations of metabolites of prostaglandin D2 (PGD2), and 1,000 1,000 •  Other AEs occurring more frequently with BG-12 than placebo were those HR: no relevant financial disclosures to declare.
plasma histamine concentrations, were measured on Days 1 and 4 for assessment 750 750 affecting the GI system.
of potential flushing mediators. 500
250
500
250
–– In the no-aspirin groups, AEs related to GI events were reported for 0/6, 3/6 and ACKNOWLEDGMENT
•  Safety evaluations, including monitoring of AEs, concomitant medication, physical 0 0 1/6 subjects receiving placebo, BG-12 BID and BG-12 TID, respectively.
examinations, 12-lead electrocardiogram (ECG) monitoring, assessments of Pre-dose 0 1 2 3 4 5 6 7 8 9 10 Pre-dose 0 1 2 3 4 5 6 7 8 9 10 –– In the aspirin groups, AEs related to GI events were reported for 1/6, 2/6 and 1/6 This study was sponsored by Biogen Idec (Weston, MA, USA). Writing and editorial support for
Time (hours) Time (hours) the preparation of this poster was provided by CircleScience (Tytherington, UK); funding was
vital signs and common hematologic, biochemical and urinary parameters were subjects, respectively. provided by Biogen Idec.
conducted throughout the study. •  Most AEs were assessed as mild or moderate in severity. For an electronic version of this poster, please scan code.

64th Annual Meeting of the American Academy of Neurology. April 21-28, 2012, New Orleans, LA, USA

28317F AAN Flushing Poster_v2M.indd 1 17/04/2012 18:01