Drawbacks of the current Multidrug Resistant (MDR) TB regimens highlighted the need of innovative therapeutic tools which could aid better management of the disease. Delamanid is a promising addition to the current treatment regimen for MDR-TB.

Tuberculosis (TB) is one of the leading causes of mortality and morbidity worldwide and India accounts for about a quarter of the global TB burden. As per the World Health Organisation (WHO) TB statistics, there were an estimated 2.79 million cases of TB in India in the year 2016.

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Management of MDR-TB - One of the Greatest Challenges

Emergence of MDR and Extensively Drug Resistant (XDR) strains has made the treatment of TB cumbersome and more challenging. As per the WHO Global Tuberculosis Report 2017, only 54% of MDR-TB patients and 30% of XDR-TB have been treated successfully worldwide.

The current treatment paradigm for MDR TB is long and expensive and involves the use of at least five drugs administered for a duration of 18 to 24 months. Sub-optimal outcomes, the association of a plethora of side effects and high rates of treatment failure further adds to the problem. Drawbacks of the current MDR TB regimens highlighted the need of innovative therapeutic tools which could aid better management of MDR-TB.

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Delamanid - A New Ray of Hope

To overcome the existing loopholes, extensive research was carried out worldwide and as a result, several novel compounds have been discovered. Delamanid is one such promising addition to the current treatment regimen for MDR TB.

Delamanid is a nitro-dihydro-imidazooxazole compound, developed by Otsuka Pharmaceuticals. In 2016, World Health Organization (WHO) updated its MDR-TB regimens classification and delamanid is presently classified in group D2 as per the new classification system. Delamanid is one of the two new drugs (Bedaquiline is the other drug) approved for the treatment of (MDR-TB) in more than four decades.

Delamanid was approved by the Drug Controller General of India in August, 2017. The drug is approved for MDR-TB in adults and children aged 6-17 years under conditional access through the Revised National Tuberculosis Control Programme (RNTCP). Delamanid use is recommended for a maximum of six months, at the recommended doses, when used with an optimised background regimen (OBR).

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The RNTCP guideline recommendations

The RNTCP guideline recommends that delamanid may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB under the following conditions:

• When an effective treatment regimen containing four second-line drugs in addition to pyrazinamide (Z) according to WHO recommendations cannot be designed
• When there is documented evidence of resistance to any FQ or second-line injectable drug in addition to MDR
• When there is higher risk for poor outcomes (eg. drug intolerance or contraindication, extensive or advanced disease)

The following Indian states were identified as initial sites for the introduction of delamanide under the RNTCP Programmatic Management of Drug Resistant TB (PMDT) through conditional access:

• Punjab
• Chandigarh
• Rajasthan
• Karnataka
• Odisha
• Kerala
• Lakshadweep

Delamanid is available to individual patients under “compassionate use” with pre-approval of Drugs Controller General of India (DCGI) upon request from the treating physician, who submits patient details for accessing the drug from Otsuka Pharmaceuticals Ltd.

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Mechanism of action

Delamanid inhibits mycolic acid biosynthesis and thus disrupts the cell wall of the mycobacterium; this, in turn, facilitates increased drug penetration through it.

Delamanid is a prodrug which is activated by the bioreduction of its nitro group by Mycobacterium tuberculosis enzyme. The resultant reactive intermediate (nitrogen oxides ) formed between delamanid and its desnitro- imidazooxazole derivative is associated with significant mycolic acid synthesis inhibition.

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Dosage

• Week 0–24: Delamanid 100 mg (two tablets of 50 mg) orally twice a day + optimised background regimen (OBR)
• Week 25 (start of month 7) to end of treatment: Second-line anti-TB drugs should be continued only as per RNTCP recommendations

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Efficacy

In a phase 2b global clinical trial, termed Trial 204, delamanid demonstrated an increased 2-month sputum culture conversion rates when added to an optimised background regimen in MDR-TB patients.

As per a study by Matsumoto et al, published in PLoS medicine, delamanid exhibits the most potent bactericidal activity, similar to Rifampicin and superior to Isoniazid.

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Safety concerns

1. A dose dependent QTcF interval prolongation has been observed with delamanid group in phase II trials; hence electrocardiography is recommended at 2 weeks, 12 and 24 weeks. Prolonged QTc interval was however not associated with syncope or arrhythmia.
2. The drug usage should be stopped if QT interval is more than 500ms. Due to the possibility of QT prolongation, the serum potassium, calcium and magnesium levels also need to be monitored.

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The World Health Organization Position Statement on the Use of Delamanid

In Jan 2018, the World Health Organization (WHO) Global Tuberculosis Programme released a Position Statement on the use of delamanid in treatment of multidrug-resistant tuberculosis (MDR-TB).

The statement was released following an expedited review of the phase III (Trial 213) randomised controlled trial results released at the 48th UNION World Conference on Lung Health in Mexico by Otsuka Pharmaceutical.

As per the final results of the phase III trial, there was no clinically relevant or statistically significant difference between the regimen containing delamanid and placebo in treatment success, all-cause mortality, and two and six month sputum culture conversion.

The phase III results did not confirm the efficacy findings of earlier studies; however the statement mentions that delamanid should be retained in country guidelines, national essential medicine lists and procurement options. In view of the trial outcomes, WHO has also recommended the need for adjustment of MDR-TB treatment algorithms.

As per the position statement, national TB programmes and other stakeholders are advised to only add delamanid to a longer MDR-TB regimen when it cannot be composed according to WHO recommendations. When an effective and well-tolerated longer MDR-TB regimen can be otherwise composed, the addition of delamanid may not be warranted.

In view of the above statement, WHO has encouraged more research on the role of delamanid in MDR-TB treatment, particularly, the use of delamanid in MDR-TB regimens compromised by drug resistance or drug intolerability. The statement concluded that data from several ongoing studies of delamanid are anticipated soon and several systematic reviews and individual patient data meta-analyses are being commissioned by WHO.