Delamanid

Delamanid in the treatment of multidrug-resistant tuberculosis

Otsuka has been engaged in anti-tuberculosis drug development efforts for over 30 years, and is the leading private sector funder of tuberculosis (TB) research and development. Delamanid (DLM), discovered by Otsu- ka’s scientists, has been shown to provide benefit with respect to short-term surrogate markers and long-term treatment outcomes, and it has received regulatory approval for treatment of adult pulmonary multidrug- resistant TB (MDR-TB) as one of only two new anti- tuberculosis drugs in the last 40 years. Lack of drug-drug interactions with major antiretrovirals and efficacy against MDR-TB allow DLM’s applicability in a wide range of MDR-TB patients. Current and future efforts are focused on replacing less safe and less efficacious second-line drugs with DLM, its contribution to all-oral and/or shortened treatment regimens, and, ultimately, inclusion in a pan-TB regimen. This manuscript provides a brief review of DLM.

KEY W O R D S : anti-tuberculosis treatment; MDR-TB; DLM; DLM for pulmonary MDR-TB

SHORTLY AFTER TAKING OVER leadership of Otsuka Pharmaceutical Co Ltd, Akihiko Otsuka (1937–2014), recognizing the persistent tuberculosis (TB) burden in Asia, chose TB as one of the company’s first research priorities.1 Following 40 years of research, delamanid (DLM) (OPC-67683) was discovered by in-house scientists in 2002 and Phase I testing began in 2004. In 2008, the first large- scale clinical trial assessing the safety and efficacy of DLM for treating multidrug-resistant tuberculosis (MDR-TB) began.2 DLM achieved its first regulatory approval in 2014 from a stringent regulatory authority,3 was subsequently included in the guide- lines for MDR-TB treatment by the World Health Organization (WHO) that same year,4 and was recognized as an essential medicine in 2015.5 DLM has also been shown to be cost-effective in MDR-TB patients.4,6

NON-CLINICAL DELAMANID DATA

DLM is an oral drug, the first in the novel class of nitro-dihydro/imidazooxazoles whose mechanism of action may be related to the inhibition of keto- and methoxy-mycolic acids.7 Nitrodihydroimidazooxa- zoles are unique relative to other compounds in the nitroimidazole class, such as nitrodihydroimidazox- azines (pretomanid, TBA 354, etc.). A key feature of DLM is that it is largely metabolized by albumin in serum, not by cytochrome P450 enzymes, and does not inhibit efflux/uptake transporters.7,8 This greatly reduces the risk of drug-drug interactions, and it has been shown that there is no clinically significant effect on DLM plasma exposure when co-administered with commonly used first- and second-line anti- tuberculosis drugs or antiretrovirals.9 Metabolism by albumin also reduces the likelihood of adverse events related to liver toxicity. Furthermore, delam- anid has a plasma half-life of 30–38 hours.3

DLM has a bactericidal mode of action against actively replicating, dormant, and intracellular TB, and against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis.7,10 Sterilizing activity has been shown to be similar to rifampicin.11 Minimum inhibitory concentrations (i.e., MIC90) of 0.012 lg/ml are noted for clinically isolated MDR-TB strains and reflect a baseline resistance of ,1% in DLM-na¨ıve patients.12 DLM is specific to the Myco- bacterium genus among bacteria and has no in vitro activity against other bacterial species.13 As it is a prodrug requiring activation by M. tuberculosis, the suspected mechanism of resistance is related to mutations in genes in the F420 biosynthetic pathway.14 The early bactericidal activity (EBA) of DLM in TB patients has been confirmed in a study.15 Four doses of DLM, 100 mg, 200 mg, 300 mg, or 400 mg, were administered as monotherapy once daily for 14 days to patients (12 patients per treatment arm) with uncomplicated, smear-positive, drug-susceptible TB.

M. tuberculosis bacterial count, measured as colony- forming units (cfu) cultured from overnight sputum samples, were used to calculate EBA, defined as a fall in log10 cfu/ml sputum/day. Safety outcomes included adverse events (AEs), clinical laboratory findings, vitals, and electrocardiogram findings. Results showed that a steady decline in cfu from baseline over the 14-day trial period was observed in all four DLM treatment groups. There were no statistically significant differences in DLM’s EBA between the four treatment groups, but a higher proportion of patients in the DLM 200 mg (80%), 300 mg (90%), and 400 mg (73%) treatment groups showed a response 70.5 log10 cfu/ml sputum decline over 14 days compared with the DLM 100 mg treatment group (45%). Pharmacokinetics of DLM are non- linear: doubling the dose results in less than twice the exposure, but optimal exposure for at least the first 2 months of treatment is achieved with twice daily dosing (Otsuka, unpublished data). Accordingly, the doses explored in the clinical program were 100 mg twice daily (i.e., 200 mg) and 200 mg twice daily (i.e., 400 mg). In the EBA study, DLM was well tolerated, treatment-emergent AEs were either mild or moder- ate in severity, and no serious treatment-emergent AEs occurred.

PHASE IIB CLINICAL STUDIES OF DELAMANID

DLM was evaluated in MDR-TB patients via a multi-site, multi-trial clinical program beginning with a 3-month randomized, double-blind, place- bo-controlled trial that included a 2-month treatment period and a 1-month follow-up (Trial 204, n ¼ 481). All patients who successfully completed Trial 204 were eligible to continue to a 6-month open- label treatment trial (Trial 208, n ¼ 213). A 24- month observational follow-up study was added (Trial 116, n ¼ 421) to assess long-term outcomes, including a supplemental mortality assessment (n ¼ 464). Patients were managed according to WHO guidelines, and long-term outcomes were assessed using standard WHO cohort definitions.16 Two- month sputum culture conversion (SCC) was deter- mined by liquid and solid media, defined as 75 consecutive weekly cultures negative for growth and no subsequent positive cultures during the follow-up period. Relying on non-randomized, open label data, long-term microbiologic outcomes using solid media culture results (in accordance with standard practices of many national TB programs) and mortality at 24 months post-randomization into Trial 204 were assessed.17–19

MDR-TB patients receiving DLM 100 mg twice daily for 2 months in combination with an optimized background regimen (OBR) demonstrated an ap- proximately 50% increase in SCC at 2 months when assessed by liquid media compared to OBR and placebo alone (64/141, 45.4% vs. 37/125, 29.6%; P ¼ 0.008].2 Similar results were observed using solid media (64/119, 53.8.4% vs. 38/113, 33.6%; P ¼ 0.002).2 Patients receiving 76 months of treatment with DLM (i.e., 6 or 8 months) in combination with OBR in the open label trial had a higher proportion of favorable outcomes (143/192, 74.5% vs. 126/229, 55%; P , 0.001) and lower mortality (6/205, 2.9% vs. 31/259, 12.0%; P ¼ 0.001) compared to patients
receiving 62 months of treatment (i.e. 0 or 2 months).17,18 MDR-TB patients achieving 2-month SCC were 3.7 times less likely to die (P ¼ 0.002),17 supporting the importance of early SCC in MDR-TB treatment.19–22

The primary safety concern with delamanid is QTcF prolongation, although its increase in clinical studies thus far has not been associated with any clinical cardiac events. Following treatment initia- tion, QTcF prolongation reaches a maximum at 8 weeks and dissipates within 4 weeks after treatment cessation.24 Co-administration with certain fluoro- quinolones and/or clofazimine appears to have a negligible effect, confirming DLM’s mild to moderate effect on QTcF prolongation.23 Overall, DLM appears to be associated with a favorable safety profile relative to other second-line anti-tuberculosis drugs.24,25

DLM was also evaluated among a nested cohort of patients in Trials 204/208/116 with extensively drug- resistant TB (XDR-TB) who were part of the MDR- TB cohort in the respective randomized 3-month and non-randomized 6-month trials.26 Patients with XDR-TB who received 76 months of treatment with DLM in combination with OBR had higher propor- tions of favorable treatment outcomes compared to patients treated for 62 months (11/17, 65% vs. 4/9, 44%; P ¼ 0.42). Consistent with the observations in the MDR-TB cohort, XDR-TB patients achieving 2- month SCC were 2.6 times as likely to have a successful treatment outcome (P ¼ 0.007).

ONGOING STUDIES OF DELAMANID

A pediatric investigational plan (PIP), agreed upon in consultation with the European Medicines Agency (EMA), has been launched to ensure the optimal use of DLM in children.Apart from completing a 10-week juvenile repeat- dose toxicity and a toxicokinetic study in rats, an age- appropriate dispersible tablet for oral suspension for children from birth to 5 years of age is under development and a bioequivalence study has been completed. At the time of writing, 13 children (median age 13 years, range 7–17) at sites in the Philippines and South Africa have been treated with the DLM tablet formulation (100 mg twice daily in treatment Group 1, for ages 12–17 years; and 50 mg twice daily in treatment Group 2, for ages 6–11 years). Initial pharmacokinetic (PK) analyses indicate that the ranges of maximum concentration (Cmax) and area under the curve for 24 hours (AUC0–24) values in these tested age groups were within the ranges observed in adult clinical trials.27 Further- more, treatment with DLM for 6 months has been well tolerated by this early cohort of pediatric patients.28 Trials that will further assess the PK and safety of the dispersible formulation of DLM in children from younger age groups are currently ongoing, with 10 children aged 3–5 years now enrolled (Trial 232, Clinicaltrials.gov identifier NCT01856634 and Trial 233, ClinicalTrials.gov identifier NCT01859923).29

DLM is also currently undergoing evaluation in seven countries (Estonia, Latvia, Lithuania, Moldo- va, the Philippines, Peru, South Africa) in a double- blind, placebo-controlled Phase III trial (Trial 213, ClinicalTrials.gov identifier NCT01424670): 511 patients aged 18–69 years with pulmonary MDR- TB were randomized in a 2:1 ratio of DLM vs. placebo in combination with OBR for 6 months, with all patients scheduled to subsequently com- plete full treatment with OBR. Within this trial, a nested human immunodeficiency virus positive
MDR-TB cohort (n ¼ 48) is being evaluated and, notably, 121 patients are being co-treated with moxifloxacin. In addition, the potential for once- daily dosing is being explored in the trial, with patients treated with DLM for the first 2 months as 100 mg twice daily, followed by 200 mg once daily for 4 months.

OTSUKA’S FIGHTBACK INITIATIVE

In early 2015, Otsuka announced its FightTBack Initiative—a broad plan to scale up programmatic use of DLM through a variety of access channels and outline Otsuka’s ongoing research and devel- opment activities. The initiative encourages the global TB community to work towards a specific goal of achieving DLM coverage for at least 20% of treated MDR-TB patients by 2020. Four pillars compile the initiative: innovative research and development, responsible access to patients, opti- mized patient management, and collaborative capacity building. Otsuka continues to work on developing new therapeutic, diagnostic and moni- toring modalities, patient support tools, and efforts to formulate DLM into a single pill dosed once daily. DLM is available for procurement to over 100 low- and middle-income countries through the Stop TB Partnership’s Global Drug Facility, with regulatory approvals achieved in the European Union, Japan, Republic of Korea and Hong Kong SAR, China, and additional regulatory activities underway in high-burden countries, including China, India, Indonesia, Philippines, Russian Fed- eration, and South Africa. Otsuka is also engaging in multiple third-party research collaborations looking at shorter, more effective and more patient-friendly ways to fight MDR-TB. With partnership support, Otsuka continues to engage in long-term capacity building through its research and medical education activities in MDR-TB,31 and facilitating the use of DLM in over 1800 patient courses distributed worldwide via compassionate use, expanded access programs, or under normal programmatic conditions.

CONCLUSION

As the leading private funder of TB research and development,31 Otsuka has invested considerable resources in research and development activities for DLM, including its pediatric studies and development of the first pediatric formulation of an MDR-TB drug. The evidence presented here, coupled with additional characteristics of the drug, makes DLM a potential candidate in the design of MDR-TB treatment regimens that are ‘clinically effective and programmatically practicable’,32 with future research and development efforts targeted towards replacing toxic and costly Group 2–4 second-line drugs, contributing to all-oral and/or shortened treatment regimens, and, ultimately, being an anchor drug in a pan-TB regimen. Uptake of DLM is critical given the number of patients likely to benefit from treatment,33 and is primarily dependent on the ability of imple- menters to overcome major obstacles, such as compliance with WHO guidance (including impor- tant pharmacovigilance parameters), strengthening local clinical capacity for use of new MDR-TB medications, and political will to explore novel treatments and optimized regimens.34 Otsuka is one of the signatories of the Declaration by the Pharma- ceutical, Biotechnology and Diagnostics Industries on Combating Antimicrobial Resistance, which restates commitments to continuing the fight against the threat of drug resistance through innovative solutions meeting public health needs and improving access to high-quality antibiotics.35 Considering the dramatic increase in bacterial resistance worldwide, and as with any anti-tuberculosis drug, rational and respon- sible use of DLM is critical to ensuring the greatest number of patients will have access to this drug over the longest period of time.36,37
Conflicts of interest: RG, JH, LJG, and NH declare being employees of Otsuka, the company that manufactures delamanid and which financed the clinical development program discussed in the manuscript. CW was an employee of Otsuka until September 2015.