24 February 2016 - Bangkok, Thailand - A new initiative to enable developing countries to access delamanid - one of two new life-saving drugs approved to combat multidrug-resistant (MDR) tuberculosis (TB) - is today announced by the Stop TB Partnership and Otsuka, the drug’s manufacturer.
The innovative public-private partnership will allow countries to access delamanid through the Stop TB Partnership’s Global Drug Facility, which already supports the USAID donation for bedaquiline -the other recently approved drug for MDR-TB, manufactured by Janssen.
MDR-TB and extensively-drug resistant TB (XDR-TB) are increasing globally. While there are existing treatment regimens to battle both types of TB, treatment for MDR- and XDR-TB can last two years or more and is extremely expensive and toxic compared to treatment for regular, drug-susceptible TB. These two new MDR-TB drugs - bedaquiline and delamanid - are the first drugs in decades with potential to dramatically improve MDR-TB treatment outcomes and reduce the number of people who die from the disease. Coordinated programmes to help access these new therapies are essential if the world is to meet the targets in the Global Plan to End TB 2016 -2020 and further the World Health Organization’s (WHO) ambitious goal to end TB as a global health threat by 2035.
All countries eligible for financing through the Global Fund to Fight AIDS, TB and Malaria and follow WHO guidelines for the proper management of MDR-TB in quality-assured programs can procure delamanid through the Global Drug Facility.
"As the largest purchaser of TB medicines for more than 100 countries, the Global Drug Facility is uniquely positioned, through coordination with public and private sectors, to catalyse uptake of new medicines and increase the speed and extent to which new TB innovations reach those who need them", said Dr Brenda Waning, Chief of the Global Drug Facility.
Delamanid will be supplied at a price of US$ 1700 for each full-course treatment of six months’ duration. The Stop TB Partnership Secretariat teams and partners will provide advocacy, technical assistance, and other services to ensure adequate financing and accelerated introduction of delamanid into national TB programs.
The public-private partnership to expedite access to delamanid will be announced and discussed at a high-level panel discussion to be held on the side of an experience-sharing workshop on the introduction of new drugs for drug-resistant TB treatment in the World Health Organization’s Southeast Asian and Western Pacific regions, taking place in Bangkok, Thailand, on February 24. The panel will bring together experts from the Stop TB Partnership’s Global Drug Facility, TB survivors, WHO Geneva, Otsuka, Janssen, and other partners to discuss how the Global Drug Facility can best work with partners to ensure increased access of these new drugs to people with MDR-TB and XDR TB as quickly and as safely as possible.
Nearly half a million people each year develop MDR-TB, and of those diagnosed and enrolled in treatment, only 50% are successfully treated. "We are committed to enhancing access to delamanid, especially in high-burden countries, while ensuring responsible use of this medicine," said Masuhiro Yoshitake, Executive Operating Officer of Otsuka and TB Global Project Leader. "This public-private partnership with Stop TB is another step forward towards realizing the goal of TB elimination."
Commenting on this new partnership, Ross Underwood, Global Access Commercial Leader from Janssen said, "The GDF plays a pivotal role in the global bedaquiline access program by virtue of its global reach, provision of quality-assured drugs, and stewardship of responsible access. We are pleased to see that the GDF will expand patient access to much needed additional treatment options and look forward to continue working together toward our mutual goal of eradicating TB."
"I think that as a TB community we need speed and a different mindset: we have 2 new drugs that can improve MDR and XDR-TB treatment outcomes - we need to make sure that these are used by all those that need them - responsibly and safely - but we must move on! We spoke about a paradigm shift in the Global Plan - this is one of the many steps we will do as Stop TB to accelerate our advance towards ending TB," said Dr Lucica Ditiu, Executive Director of the Stop TB Partnership.
Results from a Phase 2 trial showed that 45.4% of study subjects treated with delamanid 100 mg twice daily plus an optimised background regimen (OBR), developed according to WHO guidelines for treating MDR-TB, achieved sputum culture conversion (SCC) after two months compared to 29.6% of those treated with placebo plus OBR, representing a statistically significant 53% increase.[i],[ii] SCC is an indication of when a patient is no longer infectious. The more rapid clearance of TB bacilli is important since SCC at two months is strongly correlated with improved patient outcomes, including reduced mortality.
Clinical trial results demonstrated that adverse events were evenly distributed in the delamanid and placebo treatment groups with the exception of QT prolongation. Electrocardiogram QT prolongation was reported in 9.9% of patients receiving delamanid as 100 mg twice daily compared to 3.8% of patients receiving placebo plus OBR. This was not accompanied by any clinical symptoms such as syncope or arrhythmias.[ii]
A Phase 3 trial of delamanid is fully enrolled, and involves six months of treatment with delamanid plus OBR in patients with MDR-TB, including those with co-existing HIV infection. The trial is taking place in Estonia, Latvia, Lithuania, Moldova, Peru, the Philippines, and South Africa with results expected in 2018. Additionally, enrollment continues for a clinical program exploring the use of delamanid in paediatric MDR-TB and will evaluate a dispersible formulation for use with younger children and infants.
Delamanid has received regulatory approval in the European Union, Japan and the Republic of Korea and registrations are underway in China, Hong Kong, Indonesia, Philippines and Turkey. In 2014, the WHO published an interim policy guidance on "The Use of Delamanid in the Treatment of Multidrug-Resistant Tuberculosis"[iii] and in 2015 delamanid was added to the WHO’s Essential Medicines List.
Bedaquiline was discovered by scientists at Janssen and has a unique mechanism of action that inhibits mycobacterial ATP (adenosine 5'triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis. The conditional approval by the EC is supported by 24-week data from the Phase 2 clinical development programme, which included a controlled, randomised trial that evaluated the safety and efficacy of SIRTURO® versus placebo in the treatment of patients with pulmonary MDR-TB in combination with a background regimen (TMC207-C208) and an open-label study (C209). The durability of effect was supported by 120-week data from the Phase 2 controlled, randomised trial.[iv]
In Phase 2 studies, the bedaquiline treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group. The median time to culture conversion was 83 days for the SIRTURO® treatment group, compared to 125 days for the placebo treatment group at week 24 (TMC207-C208). At week 120, treatment with bedaquiline continued to result in a significantly improved culture conversion rate versus the placebo treatment group.
Furthermore, based on WHO-recommended treatment outcome definitions applied to week 120 final data, the proportion of patients defined as cured at 120 weeks was 57.6% in the SIRTURO® arm vs. 31.8% in the placebo arm (p=0.003).[v]
[i] Gler, Maria T et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012; 366(23): 2151-60.
[ii] SCC for both groups dosed with delamanid were statistically higher compared to placebo (45.4-29.6/29.6=.533) (p=.008 and p=.049). Results from the secondary analysis of SCC based on solid media were consistent with those of the primary analysis. The study found that by the end of week five, 24% and 23% of subjects in the delamanid 100 mg BID and 200 mg BID groups respectively achieved SCC compared with 13% of study subjects in the placebo group.
[iii] World Health Organization. The use of delamanid in the treatment of multidrug-resistant tuberculosis - interim policy guidance. 2014, Geneva, Switzerland. WHO/HTM/TB2014.23
[iv] Diacon A, Pym A, Grobusch M, et al. Final 120-week results of a Phase II randomised, double-blind, placebo-controlled study of 24-weeks bedaquiline treatment for MDR-TB (C208). Int J Tuberc Lung Dis 2013;17(Suppl 2):S234-5 (abstract OP-176-02).
[v] WHO. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis, Interim Policy Guidance. 2013. Available at: http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf . Accessed 07 February, 2014