No abstract

Dimethyl fumarate (Tecfidera®) is a novel oral therapy that has recently been approved for the treatment of relapsing forms of multiple sclerosis (MS) and relapsing-remitting MS (RRMS). In preclinical studies, dimethyl fumarate exhibited anti-inflammatory and cytoprotective properties that are generally thought to be mediated via activation of the nuclear factor (erythroid-derived 2)-like 2 transcriptional pathway, which is involved in the cellular response to oxidative stress. In the large, double-blind, multinational, 2-year DEFINE and CONFIRM trials conducted in over 2,600 adult patients with RRMS, twice-daily oral dimethyl fumarate 240 mg was effective in reducing the proportion of patients with MS relapse at 2 years (primary endpoint of DEFINE) and the annualized relapse rate (primary endpoint of CONFIRM) compared with placebo, with reduced disability progression also observed with the drug versus placebo in DEFINE. Dimethyl fumarate also reduced disease activity measures relative to placebo in these trials, as assessed by magnetic resonance imaging. Dimethyl fumarate was generally well tolerated in patients with RRMS; adverse events that occurred more frequently in dimethyl fumarate than in placebo recipients included flushing and gastrointestinal events. The long-term efficacy and tolerability of dimethyl fumarate is currently being investigated in the ENDORSE trial, with interim results demonstrating that dimethyl fumarate was associated with continued efficacy for up to 4 years of treatment, with no new tolerability concerns. In conclusion, although more comparative data are needed to fully establish the relative efficacy and tolerability of dimethyl fumarate compared with other therapies, oral dimethyl fumarate is an important addition to the therapeutic options available for RRMS.

A combination of prolonged-release (PR) oxycodone with PR naloxone (Targin(®), Targiniq(®), Targinact(®)) in one tablet with a fixed 2:1 ratio is available for the treatment of patients with severe pain, which can only be adequately managed with opioid analgesics. The aim of this formulation is to counteract opioid-induced constipation through the local antagonist effect of naloxone in the gut wall, while maintaining analgesia due to the low bioavailability of oral naloxone. Three large, 12-week, randomized, double-blind, phase III trials in patients with moderate to severe, chronic, non-malignant pain, plus a prospectively planned pooled analysis of two of these studies, demonstrated that oxycodone/naloxone PR improved bowel function, as measured by the bowel function index, compared with oxycodone PR. Additionally, oxycodone/naloxone PR relieved pain more effectively than placebo and no less effectively than oxycodone PR after 12 weeks. Phase II efficacy data in cancer patients are consistent with those observed in patients with non-malignant pain. Oxycodone/naloxone PR was generally well tolerated; the most frequently reported adverse events were of gastrointestinal origin, consistent with those known to occur with opioid therapy. Of note, numerically lower rates of constipation were observed in the oxycodone/naloxone PR group compared with the oxycodone PR group. A cost-utility analysis predicted that oxycodone/naloxone PR would be a cost-effective option compared with oxycodone PR in patients with non-malignant pain. Although more comparative data are needed, oxycodone/naloxone PR is an effective option for use in patients with severe chronic pain, particularly among those with opioid-induced constipation.

Rivaroxaban (Xarelto(®)), an oral direct factor Xa inhibitor, is approved for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the prevention of recurrent DVT and PE. It is administered at a fixed oral dose and does not require routine coagulation monitoring. In the EINSTEIN-DVT and EINSTEIN-PE trials, in over 8,000 patients with DVT and/or PE, a single-drug approach with rivaroxaban was shown to be noninferior to standard therapy consisting of subcutaneous enoxaparin sodium overlapping with and followed by an oral dose-adjusted vitamin K antagonist (enoxaparin-VKA) with regard to the incidence of symptomatic recurrent venous thromboembolism (VTE) after 3, 6 or 12 months of treatment. Rivaroxaban was generally well tolerated in patients with DVT or PE, with no significant between-group differences in clinically relevant bleeding between the rivaroxaban and enoxaparin-VKA groups. Notably, rivaroxaban was associated with a significantly lower rate of major bleeding compared with enoxaparin-VKA when EINSTEIN-DVT and EINSTEIN-PE data were pooled. Pharmacoeconomic analyses indicated that rivaroxaban may be a cost-effective alternative to enoxaparin-VKA for the treatment of DVT or PE and prevention of recurrent VTE. Extended prophylaxis with rivaroxaban reduced the incidence of symptomatic recurrent VTE to a greater extent than placebo in the EINSTEIN-Extension trial, but was associated with a non-significant increase in the risk of clinically relevant bleeding compared with placebo. In conclusion, rivaroxaban is a reasonable alternative to standard therapy for the treatment of DVT and PE, and as extended thromboprophylaxis.

Trifluridine/tipiracil (Lonsurf(®)) is a novel, orally active, antimetabolite agent comprised of trifluridine, a thymidine-based nucleoside analogue, and tipiracil, a potent thymidine phosphorylase inhibitor. Trifluridine is incorporated into DNA via phosphorylation, ultimately inhibiting cell proliferation. Tipiracil increases systemic exposure of trifluridine when coadministered. Trifluridine/tipiracil has recently been approved for the treatment of adult patients with metastatic colorectal cancer (mCRC) who are refractory to or are not considered candidates for, current standard chemotherapy and biological therapy in the EU and USA and in unresectable advanced or recurrent CRC in Japan. The approved regimen of oral twice-daily trifluridine/tipiracil (35 mg/m(2) twice daily on days 1-5 and 8-12 of each 28-day cycle) significantly improved overall survival and progression-free survival and was associated with a significantly higher disease control rate than placebo when added to best supportive care in the multinational, pivotal phase III trial (RECOURSE) and a phase II Japanese trial. Trifluridine/tipiracil was associated with an acceptable tolerability profile, with adverse events generally being managed with dose reductions, temporary interruptions in treatment or administration of granulocyte-colony stimulating factor. The most common grade 3-4 adverse events (≥10 %) were anaemia, neutropenia, thrombocytopenia and leukopenia. In conclusion, trifluridine/tipiracil is a useful additional treatment option for the management of mCRC in patients who are refractory to, or are not considered candidates for, currently available therapies.