Need for expanded access to two promising MDR TB drugs
Nathan Geffen, Centre for Social Science Research, UCT
Two experimental drugs for the treatment of MDR TB have completed phase II clinical trials. While neither is ready yet to be registered with a regulatory authority, bedaquiline (formerly TMC207, manufactured by Tibotec) is already better tested than most second-line TB drugs and has a good side-effect profile. The results of a Phase II trial of delamanid (formerly OPC-67683, manufactured by Otsuka Pharmaceuticals) are expected to be published soon.
HTB previously reported the development of bedaquiline and Phase II trial results [1,2]. Tibotec reported further results at a Critical Path to TB Drug Regimens meeting in Arlington in November. In this trial of 160 MDR TB patients, that compared an optimised background regimen plus either placebo or bedquiline, there was faster culture conversion in the bedaquiline arm by 24 weeks (p=0.003). This was the primary endpoint. In secondary analyses, median time to culture conversion was 12 weeks vs 18 weeks. And at 24 weeks 79% of bedaquiline patients vs 58% of placebo ones had converted to sputum-negative (p=0.008). Side effects were distributed evenly over the two groups. There were no serious study drug-related side effects nor were there clinically significant differences in laboratory results. QT prolongation was seen on the bedaquiline arm, but there were no adverse events associated with this nor were there any prolongations greater than 500 milliseconds. 
In an ongoing open-label study (C209) that is assessing safety, efficacy and tolerability over two years of bedaquiline in smear-positive MDR TB patients, there was an 80% response rate at 24 weeks. Resistance to more drugs was associated with poorer response rates (56% for XDR, 77% for pre-XDR and 87% for MDR; p=0.0006). Patients with no cavitations also responded better (p=0.0157), as did patients on three or more potentially active drugs (p=0.0376). The most frequent side effects were nausea (11%), arthralgia (12%) and hyperuricaemia (14%). About 2% of the patients stopped bedaquiline due to an adverse event.
Tibotec has planned a Phase III superiority study (C210) with 600 subjects. The primary endpoint is intended to be relapse free cure at 15 months and a final analysis will also be done at 21 months.
The company is also considering a paediatric trial of 60 children to examine PK and safety.
The company has a compassionate use/expanded access programme. In countries that have a mechanism to authorise pre-approval access of unregistered medicines, patients with pre-XDR or XDR TB at what the company describes as validated centres can obtain bedaquiline. In countries where this is not feasible, such as China, Russia and Lithuania, an expanded access trial is planned. But at the time of the Critical Path meeting when this was presented, fewer than 30 patients had accessed the drug via compassionate use or expanded access.
In a phase II trial (Trial 204), about 480 patients with MDR TB were divided into three arms, stratified by disease severity. All patients received optimised background regimens. The first group received placebo, the second delamanid 200mg/day and the third delamanid 400mg/day for eight weeks. Patients were followed for an additional four weeks for safety and to confirm sputum conversion. The trial took place at 15 sites in 9 countries. Those patients who successfully completed Trial 204 were eligible to enroll in a 26 week open label protocol. Those who participated in Trial 204 and received placebo therefore had 26 weeks exposure to delamanid and those who received delamanid in trial 204 had a total of 34 weeks exposure to delamanid. 
Otsuka is currently recruiting for a Phase 3 trial to test the safety and efficacy of delamanid 200mg daily. 
These two drugs are the furthest along in the pipeline to treat drug-resistant TB. It is essential that they soon be tested together, so that if or when they are approved clinicians do not have to grapple with whether or not to add a single drug to failing regimens.
TB drug development is painfully slow. Consider that rilpivirine (TMC278), an antiretroviral of minor importance, was presumably discovered after bedaquiline (given that TMC278 signifies a chronologically later drug than TMC207). Yet the rilpivirine phase III trial started in 2008 and the FDA approved the drug last year. In contrast, bedaquiline is not expected to be registered in the very near future. This is not to single out Tibotec: indeed their TB development is the most advance. But this example shows the comparative lack of resources invested in getting TB drugs to market. Regulatory hurdles specific to TB worsen the situation. For example, some regulators want to see two-year relapse rates before granting approval.
Pre-regulatory approval expanded access should be a priority. Tibotec has committed to this but because of regulatory hurdles, lack of knowledge about the programme and perhaps lack of urgency from the company, we remain far from significant expanded access. It is unclear what commitment Otsuka has to expanded access.
Activists and patients must increase the pressure on Otsuka, Tibotec, health ministries and service providers to make these drugs available more widely for pre-approval access. More pressure must be put on the entire industry to develop more drugs, though as recent TAG/i-Base pipeline reports show, this is starting to improve.
- Geffen N. 2009. TMC207 reduces time to sputum conversion in phase II trial on patients with drug-resistant TB. HTB 10(7) July/August 2009.
- Clayden P. 2011. Faster conversion rates with TMC-207 versus placebo plus OBT for the treatment of MDR-TB. HTB 12(1-2) January/February 2011.
- Presentation by Tibotec to Global TB Community Advisory Board at CPTR 2011.
- Otsuka. A Placebo-controlled, phase 2 Trial to Evaluate OPC 67683 in patients with pulmonary sputum culture-positive, multidrug-resistant tuberculosis (TB).
- Otsuka. Safety and efficacy trial of delamanid for 6 months in patients with multidrug resistant tuberculosis.