Long road to effective TB treatment hits speed bumps: Regulatory refusal of one TB drug candidate, stalled progress on another

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EMA Delamanid refusalMomentum toward gathering an effective arsenal of treatment for tuberculosis may have gathered speed in recent years, the 2013 Pipeline Report jointly released by the Treatment Action Group and HIV i-base in June pointed out, yet it falls far short of what people sick and infected with TB worldwide need now.

Case in point, the report noted, was the status of delamanid, a new medicine in development for treatment of drug-resistant strains of tuberculosis. It had advanced further in clinical trials than bedaquiline, which became the first new approach to treating TB to receive regulatory approval in nearly half a century when the FDA approved that drug in December. But while delamanid had shown encouraging results in those trials — markedly lower mortality for those taking it than for those not given the drug — and had been submitted to the European Medicines Agency in late 2011, it had yet to receive regulatory approvals that would allow it to begin to be used for patients. Adding to the impetus for progress on delamanid — the nearest new contender, a drug called sutezolid, lags even further behind, “thwarted by slow activity of its sponsor,” which was, at that point, the pharmaceutical giant Pfizer, the report noted.

On Friday, the European Medicines Agency issued a statement refusing authorization to market delamanid for treatment of drug resistant tuberculosis, saying the benefits of delamanid “had not been sufficiently shown” and  “did not outweigh its risks.” At the same time the agency said the decision would have no impact on patients currently enrolled in clinical trials taking the drug. While the most serious side effect discovered in patients taking delamanid was a prolonged period between heartbeats, that did not lead to health-threatening problems, according to researchers, Other side effects that included nausea, and headache, occurred at comparable rates among patients on standard regimens. At the same time while two of 192 patients —  1 percent —  taking the drug for six months died, the comparable mortality rate for those on existing regimens is in the range of 10 to 15 percent, according to researchers.

TAG responded to the agency’s decision with statement calling it “myopic and deeply disappointing.” Among the benefits the EMA was denying the patients, TAG’s statement said, is “a possible survival advantage.” In addition, trials had shown that the drug, in combination with other medicine could shorten the amount of time that patients could spread tuberculosis to others, the statement noted.

Keeping delamanid out of patients’ reach, the statement also noted, could endanger the  approved bedaquiline, making it the only new addition to failing regimens for patients with drug resistant strains and increasing the possibility that strains of disease could grow resistant to that treatment as well.

Otsuka, the company that filed for EMA approval can request “re-examination” of the refusal within 15 days, the EMA’s statement says. TAG, in turn, concluded its statement urging the EMA to reconsider its decision.

In the meantime, earlier this month the Maryland-based pharmaceutical company Sequella announced that it had acquired rights to develop the lagging sutezolid from Pfizer, which had scaled back its work on drugs for infectious diseases. TAG is urging sutezolid’s new developer to up the pace of getting that drug out the door, by working with not-for-profit research consortia that can add resources to the process by including it in combination studies. Such collaborations, TAG’s letter to Sequella CEO Dr. Carol Nacy says, will make the most of investments so far, as well as future investments in the drug. TAG representatives hope to discuss ideas for accelerating sutezolid’s development further in a meeting with Sequella leaders later in the month.

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