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R&D round-up: selumetinib, tedizolid and tofacitinib trial results

By News team

MAPK pathway inhibitor shows promise in ovarian cancer

Women with a particular type of recurrent ovarian cancer might benefit from treatment with MAPK pathway inhibitors, such as selumetinib, a small study suggests ( 2013;14:134).

The open-label, phase II trial involved 52 women with recurrent low-grade serous ovarian or peritoneal carcinoma, types of cancer that are resistant to cytotoxic chemotherapy but have a high frequency of MAPK pathway mutations. Selumetinib hydrogen sulphate, a potent MAPK pathway inhibitor, was administered orally in four-week cycles of 50mg twice daily, and was well tolerated with 15 per cent of patients achieving at least partial treatment response. There were no treatment-related deaths but several grade 3/4 toxicities.

Inhibitors of the MAPK pathway should be further investigated in patients with low-grade serous carcinomas of this kind, say the researchers. "In view of the robust activation of the MAPK pathway in [this disease], molecular targeting of this pathway provides a logical treatment option for patients."

Tedizolid as good as linezolid

Antimicrobial agent tedizolid phosphate is as good as linezolid at treating acute skin infections, research suggests ().

In the phase III, double-blind non-inferiority trial, adults with acute bacterial skin and skin structure infections were randomly allocated to receive 200mg of tedizolid once daily for six days (n=332) or 600mg of linezolid twice daily for 10 days (n=335).

Some 80 per cent of patients in each treatment group achieved an early treatment response, defined as no increase in lesion surface area and an oral temperature of 37.6C or below at the 48–72 hour assessment (treatment difference 0.1 per cent, 95 per cent confidence interval -6.1 to 6.2 per cent).

Treatment response rates were also similar between the two groups at day 11 of treatment and one-to-two weeks after treatment ended. Adverse events were comparable between the two groups.

Tedizolid was non-inferior to linezolid, within the 10 per cent noninferiority margin, and may be a reasonable treatment alternative for these patients, the authors conclude.

They point out that there are uncertainties regarding the primary efficacy endpoints that should be used in non-inferiority studies of treatments for acute skin infections.

Tofacitinib an option for treatment-refractory RA patients

Tofacitinib with methotrexate improves rheumatoid arthritis (RA) symptoms with "manageable" adverse events in otherwise treatment-refractory patients, a Pfizer-run phase III trial suggests ().

The six-month, double-blind trial involved 399 adults with moderate-to-severe RA and inadequate response to tumour necrosis factor inhibitors. Patients were given methotrexate twice-daily oral tofacitinib 5mg, tofacitinib 10mg or placebo.

Compared with placebo, both doses of tofacitinib were associated with improvements in all of the primary and secondary outcomes — which included disease activity scores and response rates on the American College of Rheumatology scale.

Tofacitinib’s safety profile was consistent with previous phase II and III studies (PJ 2012;289:174 and PJ 2011;287:435), the authors say. Further studies are needed to establish the long-term safety and efficacy of the drug, and explore how it causes the lipid increases that are seen with treatment.

An accompanying (ibid, p429) agrees that further safety data are needed. Infectious diseases are the major risk of treatment, explained by the effect that tofacitinib — a janus kinase inhibitor — has on innate and acquired immunity. The drug’s effect on liver function will also need to be carefully monitored.

"After methotrexate and biotherapies, oral treatment with signalling inhibitors could represent the next milestone in RA treatment," it concludes.

Citation: Electronicjuice DOI: 10.1211/PJ.2013.11117132

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