CONCLUSION-DISCUSSION Efficacy and Tolerability of Fingolimod, Dimethylfumarate, and Teriflunomide in Patients with Multiple Sclerosis: Real World Experience from Single Center NgocHanh Vua, Michael Bradshawb, Harold Mosesb, Subramaniam Sriramb, Siddharama Pawateb Departments of aPediatrics, bNeurology, Vanderbilt University Medical Center, Nashville, TN INTRODUCTION RESULTS Three orally bioavailable immunomodulatory agents have been FDA approved for the disease modifying treatment of multiple sclerosis. The approval was based on the favorable results in pivotal phase III clinical trials. While randomized clinical trials (RCTs) are the gold standard in determining the safety and efficacy of therapeutic agents, observational studies yield complementary information. We report our experience with orally bioavailable MS therapies and their efficacy in preventing clinical and MRI relapses, as well as common side effects and secondary impact on duration of therapies. ** Fingolimod: In placebo-controlled trials (Fingolimod at 0.5mg daily), most common side effects include: headache (25%), liver enzyme elevation (15%), diarrhea (13%), cough (12%), sinusitis (11%), influenza (11%), abdominal pain (11%), back pain (10%), HTN (8%), lymphopenia (7%), blurred vision (4%), bradycardia (3%), skin papilloma (3%), and basal cell carcinoma (2%). Elevated liver enzyme and basal cell carcinoma are the two most common adverse events leading to discontinuation of Fingolimod. ** Teriflunomide: In placebo-controlled trials (with Teriflunomide 14mg), most common side effects are headache (16%), elevated ALT (15%), diarrhea (14%), alopecia (13%), nausea (11%), paresthesia (9%), arthralgia (6%), neutropenia (6%), and hypertension (4%) (4). Elevated ALT is the most common adverse reaction leading to discontinuation. ** Dimethylfumarate: In placebo-controlled trials, most common side effects reported for DMF at 240mg twice daily include flushing (40%), abdominal pain (18%), diarrhea (14%), nausea (12%), vomiting (9%), pruritus (8%), lymphopenia (2%). 4% of patients treated with Tecfidera® discontinued medication due to GI side effects while 3% of patients stopped Tecfidera® secondary to flushing. 1% of patients discontinued DMF secondary to elevated hepatic transaminases TERIFLUNOMIDE: 98 patients(78 females, 20 males, age 49 ± 9.3 years) were on treatment for 20.2 ± 13.3 months. 17 patients (17%) had clinical relapses while MRI relapses occurred in 9 (9%). 22 patients (22%) discontinued due to side effects including GI (36%), rash (14%), hair loss (9%), infections (9%), HTN (9%), paresthesia (9%), and one patient reports tongue pain as reason for discontinuation. DIMETHYLFUMARATE: 192 patients (146 females, 46 males, age 43 ± 11 years) were on treatment for. 16 ± 9 months. 33 patients (17%) had clinical relapses while MRI relapses occurred in 10 (5%). 38 patients (20%) discontinued due to side effects including GI upset (71%), flushing (10%), rash (5%), leukopenia (2%), headache (2%), and mood change (2%). FINGOLIMOD: 206 patients (151 females, 55 males, age 41 ± 9.4 years) were on treatment for 20.7 ± 16 months. 22 patients (11%) had clinical relapses while MRI relapses occurred in 8 (4%). 26 patients (13%) discontinued due to side effects including lymphopenia (ALC< 300) (23%), elevated LFTs (9%), headache (5%), HTN (2%), cough (2%), macular edema (1%), bradycardia (1%), and rash (0.5%)   Teriflunomide (Aubagio) Dimethylfumarate (Tecfidera) Fingolimod (Gilenya) N 98 192 206 Females 78 146 151 Males 20 46 55 Age (years) 49 ± 9.3 43 ± 11 41 ± 9.4 Pre-EDSS avg ± SD 2.8 ± 1.9 2.0 ± 1.8 2.1 ± 1.8 Pre-25 foot walk avg ± SD 8.8 ± 9.2 7.4 ± 6.8 6.9 ± 4 Post-EDSS avg ± SD 2.0 ± 1.9 2.2 ± 1.9 Post-25 foot walk avg ± SD 8.5 ± 9.8 6.9 ± 5.0 7.5 ± 6.4 # avg months on medication ± SD 20.2 ± 13.3 16 ± 9 20.7 ± 16 %MRI relapse 9/98 (9%) 10/192 (5%) 8/206 (4%) %Clinical relapse 17/98 (17%) 33/192 (17%) 22/206 (11%) Early discontinuation due to side effects 22/98 (22%) 38/192 (20%) 26/206 (13%) # avg months to discontinue 5.1 ± 6.6 6.2 ± 6.7 11 ± 8.8 No side effects 50/98 (51%) 90/192 (47%) 100/206 (49%) METHODS We reviewed Vanderbilt MS Center patient database and identified patients who had been switched to one of the oral medications. All patients were regularly followed by one of our neurologists at the MS center (HM, SP, and SS). We conducted a retrospective chart review of all these patients (cut off time point is September 2015), recorded 25-foot walk and EDSS score prior switch to oral agent, reason for switch, 25-foot walk and EDSS after switch, age of patient at switch, number of clinical and brain MRI relapses on oral agents, duration (number of months) on these oral agents, reason(s) for discontinuation of therapies, and noting common reported side effects (whether clinical and/or monitoring labs). A clinical relapse is defined as a change in neurological examination with an expanded disability status score (EDSS) increase of 1 point or an increase of functional system score (FSS) of 2 points. Brain MRI relapse is defined as presence of contrast enhancing lesions (CEL). CONCLUSION-DISCUSSION Relapses while on oral MS medications were comparable to clinical trials, but adverse effects affected patients at higher rates than in clinical trials Overall, disease modifying therapies with GI side effects are not as well tolerated as compared to agents without GI impact, leading to poor compliance and early discontinuation. Possible explanations for our center seeing a higher rate of adverse effects leading to discontinuation of medications as compared to clinical trials include (i) patients enrolled in clinical trials may be motivated to persevere in the face of adverse effects (ii) inadequate counseling about adverse effects and (iii) inadequate supportive measures to alleviate adverse effects REFERENCES Sorenson HT et al, HEPATOLOGY 2006;44:1075-1082 Nallamothu BK et al Circulation. 2008;118:1294-1303 Siddharama Pawate and Francesca Bagnato. Newer Agents in the Treatment of Multiple Sclerosis. The Neurologist 2015; 19:104-117. 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