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Original approach to multidrug-resistant tuberculosis

Qurient is poised to put Q203, a first-in-class drug candidate that targets multidrug-resistant tuberculosis, in phase 2 testing by the end of 2017, and is now looking for a partner.

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Jun 01, 2017
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Multidrug-resistant tuberculosis (MDR TB) has been described by the World Health Organization (WHO) as a ‘public health crisis’. In 2015, there were an esti­mated 480,000 new cases of MDR TB, and 210,000 deaths were caused by the disease, which is defined by resistance to either Nydrazid (isoniazid) or Rifadin (rifampin), the two most effective TB treatments. An additional 100,000 people have rifampin-resistant TB. In addition, approximately 9% of MDR TB cases are believed to be extensively drug-resistant (XDR), which entails additional resistance to any fluoroquinolone and to at least one injectable second-line drug.

Consequently, new therapeutic strategies are needed to combat both MDR and XDR strains of the disease. In recent years, two new drugs active against drug-resistant TB have been released: Janssen Therapeutics’ Sirturo (bedaquiline), approved by the US Food and Drug Administration (FDA) in 2012 and by the European Commission in 2014, and Otsuka Pharmaceutical’s Deltyba (delamanid), which was approved in 2014 in Europe, Japan and South Korea. Both drugs are on WHO’s List of Essential Medicines. However, new MDR and XDR drugs homing in on different targets, to be used in combination with existing treatments, are needed, as Mycobacterium tuberculosis can develop resistance rapidly (Fig. 1).

Figure 1: Scanning electron micrograph of Mycobacterium tuberculosis.

Qurient Co. Ltd., a South Korean company founded in 2008, has a promising first-in-class clinical candi­date, Q203, that fills this need. Q203 is an imidazopyri­dine amide that blocks the growth of M. tuberculosis by targeting QcrB, the cytochrome b subunit of the respiratory cytochrome bc1 complex.

The compound was originally discovered by researchers at the Institut Pasteur Korea in collabora­tion with researchers at INSERM, and was in-licensed by Qurient in March 2010. Q203 is easily synthesized in one sequential amide-coupling step with 6-chloro- 2-ethylimidazo[1,2-a]pyridine-3-carboxylic acid and (4-(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl) phenyl)methanamine. The drug has no chiral center, is amenable to large-scale synthesis and has a low cost of goods, which is an advantage for people in low-income countries, who are disproportionately affected by tuberculosis.

In a paper published in Nature Medicine in 2013, Kevin Pethe, Kiyean Nam, Jaeseung Kim and col­leagues from institutions across the globe, including Qurient, reported that in preclinical studies Q203 showed a novel mechanism of action involving the inhibition of ATP synthesis and cytochrome bc1 activity1. Indeed, it inhibited the growth of both MDR and XDR M. tuberculosis clinical isolates in culture broth in the low nanomolar range and was effica­cious in a TB mouse model at a dose less than 1 mg per kg body weight. Moreover, the authors reported that Q203 has pharmacokinetic and safety profiles that are compatible with once-daily dosing.

Success in the clinic

Qurient has successfully completed a single-ascend­ing-dose study of Q203 (up to 800 mg) in 56 healthy volunteers in the United States and is currently test­ing the drug in a multiple-ascending-dose study in healthy volunteers. The company intends to start a phase 2a trial in drug-naive patients in South Africa by the end of 2017 and is now ready to look for partners to help move the programs forward.

“We are ready to partner for the later-stage stud­ies and ideally with a global codevelopment partner that has a willingness to bring the drug to market. Otherwise we would be willing to work with local distributors in some of the emerging markets such as China and Southeast Asia,” explained Kiyean Nam, Qurient’s CEO. In 2014, Qurient granted Infectex, Ltd., a Russian biotech in the Maxwell Biotech Venture Fund portfolio, exclusive rights to develop and com­mercialize Q203 in the Russian Federation, Armenia, Belarus, Kazakhstan, Kyrgyzstan, Moldova, Tajikstan, Turkmenistan, Uzbekistan and Ukraine.

Originally financed by ten Korean venture capital companies and the Novartis Venture Fund, Qurient went public in 2016 and raised an additional $35 million, bringing the total it has raised to date to just under $75 million. “We will be able to fund the phase 2a study for sure and could also do the phase 2b trial by ourselves,” noted Nam.

Negotiating partnerships

With Q203 addressing a major medical need, especially in emerging countries, Qurient intends to secure a Priority Review Voucher (PRV) from the FDA, which Nam believes will be a strong bargaining chip in partnership discussions. “We could go for a conditional new drug application after the phase 2b and therefore would expect potential partners to take the value of the PRV into account when discussing a codevelopment deal,” he added. If Qurient went down the multiple-partnership route with local companies, Nam would want them to contribute to the costs of pivotal studies.

Nam said Q203 will be used in combination with other TB drugs, and so it is likely that it will have to be tested with them. “We have not yet decided which compound we will combine Q203 with but think it would probably be best if we opted for one of the newer ones,” he explained.

With the preclinical evidence the company has in hand, Nam is confident that the compound will be an effective treatment for MDR and XDR TB, and he anticipates that it could be ready to be given to patients as early as mid-2018. “So now is a good time to start partnering discussions,” he added.

  1. Pethe, K. et al. Nat. Med. 19, 1157–1160 (2013).

Contact:

Kiyean Nam, CEO
Qurient Co., Ltd.
Seongnam, Republic of Korea
Tel: +82 31 8060 1600
Email: knam@qurient.com
Website: www.qurient.com


Go to the profile of Qurient Co., Ltd.

Qurient Co., Ltd.

Qurient is a ‘Network R&D company’ mainly focuses on development of novel therapeutics from late discovery to human proof of concept. Qurient has expertise in virtual R&D project management and operates through extensive network of research organizations.

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