Teriflunomide ( Aubagio ) has a well characterized safety and tolerability profile that is consistent across phase II and III studies in the Teriflunomide clinical development program.
Overall, adverse events typically reported more frequently with Teriflunomide than placebo included hair thinning, nausea and alanine aminotransferase ( ALT ) increase.
In addition to these, among the most common adverse events reported are nasopharyngitis, paresthesia, back pain, limb pain, diarrhea, headache, upper respiratory tract infection and arthralgia.
These adverse effects were of mild to moderate intensity, self-limiting and infrequently resulted in treatment discontinuation ( 5–16% of patients ). Treatment discontinuations in all groups were most frequently related to increased ALT concentration and were driven by protocol-mandated discontinuation in the event of increased ALT.
Five deaths were reported in the core studies: three in the Teriflunomide treatment groups in TOWER [ n = 1, 7 mg ( traffic accident ); n = 2, 14 mg ( suicide and septicemia ) ] and two in the placebo groups in TOWER ( n = 1, respiratory infection ) and TOPIC ( n = 1, suicide ); none were considered by the investigator to be causally related to Teriflunomide treatment.
The safety and tolerability profile of Teriflunomide remained consistent with continued long-term exposure for up to 13 years in extension studies.
Safety data derived from the phase II, TEMSO, TOWER and TOPIC core studies, as well as long-term extension data from the phase II and TEMSO studies, represent over 12 years of treatment duration with a cumulative exposure to Teriflunomide of more than 6800 patients-years.
Safety data from the individual TOWER, TOPIC and TENERE extensions ( up to 7 years ) have also demonstrated a consistent safety profile relative to other Teriflunomide studies.
Adverse effects were generally mild to moderate in intensity. Across all studies, less than 23% of patients reported adverse effects that led to permanent treatment discontinuation; most were protocol-mandated discontinuations due to ALT elevations.
An additional 15 deaths were reported in the phase II ( n = 2; tachycardia and myocardial infarction ), TEMSO ( n = 7; colon cancer, cardiac arrest, malignant melanoma, acute heart failure, bleeding from duodenal ulcer and two deaths from an unknown cause ) and TOWER ( n = 6; pulmonary tuberculosis, pulmonary embolism, hematemesis, sepsis and two cases of suicide ) extension studies.
Two deaths ( pulmonary tuberculosis and suicide; both in TOWER ) were considered to be potentially related to treatment.
Neutrophil and lymphocyte reductions were observed in the core phase II and III studies, although mean counts remained within normal ranges and stabilized on treatment; actual mean decrease was up to 15%.
In the extensions, neutropenia and leukopenia were reported in less than 6% of patients receiving Teriflunomide for up to 9 years and were not associated with serious or opportunistic infections.
No hematologic malignancies were reported.
These data have demonstrated that long-term treatment with Teriflunomide is not associated with any deleterious effects with respect to protective immunity.
In comparison with Fingolimod or DMF ( Dimethylformamide ), Teriflunomide has a less pronounced effect on lymphocyte count.
In FREEDOMS and FREEDOMS II, Fingolimod reduced mean lymphocyte counts by over 70% from baseline during the first month of treatment, whereas DMF reduced lymphocytes by 28% to 32% in the DEFINE and CONFIRM studies.
In long-term studies with Fingolimod, lymphopenia was a commonly reported adverse effect, occurring in 15.5% of patients ( FREEDOMS extension, data to 54 months ).
This contrasts with 0.8% of patients experiencing lymphopenia in the Teriflunomide clinical trials ( data to 12 years ).
Although lymphopenia was an uncommon event in DMF trials, it was considered to be significantly associated with treatment [ risk ratio ( 95% confidence interval ), 5.69 ( 2.40–13.46 ); p less than 0.0001 versus placebo ].
Lymphopenia is also believed to be a risk factor for opportunistic infections such as PML ( progressive multifocal leukoencephalopathy ) in patients receiving DMF.
To date, there have been four instances of PML in DMF-treated patients ( although not always in the context of prolonged marked lymphopenia ).
Nine postmarketing reports of PML have also been documented in patients receiving Fingolimod with no prior Natalizumab treatment.
No cases of PML have yet been reported in Teriflunomide-treated patients. ( Xagena )
Miller AE, Ther Adv Neurol Disord 2017; 10: 381–396