Tuberculosishttp://goehlmann.infoDevelopments related to the anti-tuberculosis compound Bedaquiline (originally called R207910 and TMC207).Fri, 13 Feb 2015 17:08:43 GMTFri, 13 Feb 2015 17:08:43 GMTTuberculosisFuguHub1440<![CDATA[Bedaquiline for Patients with NTM Lung Disease?]]> Structure of TMC207/R207910

The journal Chest has recently published an article describing an off-label use of Bedaquiline (TMC207/R207910). Philley et al. have explored the effects of the drug in patients with nontuberculous mycobacterial (NTM) lung disease. They treated in total 10 patients with the same bedaquiline dosage used in TB trials.

While the authors clearly point at the small sample size of the study, they did not observe abnormal EKG findings - something which is of concern as the drug has a black-box warning for arrhythmias (=> long QT syndrome).

I hope we will be able to quickly gather more information over potential long QT risks so that we get a better view on the risk/benefit balance.

You can find the article here:

TuberculosisFri, 13 Feb 2015 17:08:43 GMT
<![CDATA[Toxic tuberculosis drug]]> Structure of TMC207/R207910

I admit I am biased. I have contributed to our understanding of the molecular mechanisms of bedaqueline and wish the drug to become a successful aid in curing patients with MDR-TB. Therefore I was concerned and curious to learn more when I saw this heading twice on 31st of December:

"New treatment strategy allows lower doses of toxic tuberculosis drug without compromising potency"

Of course, learning that a person is working in / for the pharmaceutical industry triggers a broad spectrum of associations with different people. Similarly, for me reading characterizations such as "toxic tuberculosis drug" or "higher toxic doses of bedaquiline" bring up associations of bad news as you would not want people to be treated with "toxic drugs".

After reading the articles I came to realize that the choice of words for the heading might have been too strong as also one of the authors (Dr. Gupta) states in an interview: "In a phase 2 trial involving patients with advanced MDR-TB, a significantly higher number of participants receiving bedaquiline died than those receiving placebo although the causes of mortality were not directly attributable to the drug."

Over the next two days I stumbled across two more sites referring to the same research. Here the headings read a little differently: "Hypertension Medication May Enhance Tuberculosis Treatment" and "Study indicates new strategy to treat tuberculosis".

Choosing the right words for a heading sure is difficult - especially when they concern words that elicit an emotional response in some readers. To me "toxic" is one of them.

Here are the articles I am referring to:

TuberculosisFri, 02 Jan 2015 21:38:46 GMT
<![CDATA[120 week results of Bedaquiline phase 2 study]]> Structure of TMC207/R207910

The New England Journal of Medicine has just published the results of the Bedaquiline (TMC207/R207910) phase 2 study by Diacon et al. Having analysed the data after 120 weeks, the researchers demonstrated a statistically higher cure rate in patients infected with multi-drug resistant tuberculosis (MDR-TB) compared to placebo: nearly twice as many MDR-TB patients were cured when given bedaquiline.

In a second article, Edward Cox and Katherine Laessig of the FDA looked at the benefit-risk balance for treating drug-resistant tuberculosis also in the context of the finding that more patients in the bedaquiline group died than in the placebo group.

While the number of people who died in the bedaquiline is still small ("Among the 4 other patients in the bedaquiline group who died, there was no apparent common cause of death".), this is certainly of concern. Even though Cox and Laessig remark that "[...] the length of time between the last receipt of bedaquiline and death makes it difficult to discern a mechanism by which bedaquiline could be directly related to the deaths, even if we take bedaquiline's long half-life into consideration.", I hope we will be able to quickly either identify a link with bedaquiline or obtain information that show that these deaths were not linked to the use of bedaquiline.

Even more so as they remark that "The previously cited historical data show that outcomes are very poor in patients who do not receive adequate treatment."

Here are both articles:

TuberculosisFri, 22 Aug 2014 09:33:02 GMT
<![CDATA[Bedaquiline induces the dormancy regulon]]> Structure of TMC207/R207910

We have just published in “Nature Communications” new results that may contribute to our understanding of the working mechanism of our compound Bedaquiline (TMC207/R207910) against Mycobacterium tuberculosis. We have especially investigated why it takes more time for the compound to kill the bacteria ("[...] early bactericidal activity during the first week of chemotherapy is minimal").

Identifying such early bactericidal activity has been used for many decades in the clinic as an indicator for the efficacy of a new compound. Accordingly, if the early effects are low, this has been seen as a disadvantage for the further development of a compound. An obvious reason is that clinical trials need to last longer to proof efficacy - which is of course more expensive.

Our data suggests that as a consequence of treatment with Bedaquiline - which inhibits the ATPsynthase of the TB bacteria and thereby reduces the available energy supply - the bacteria adjust aspects of their metabolism in an attempt to survive the energy shortage. Furthermore, using Affymetrix microarrays we show data that suggest an induction of the dormancy regulon. These findings may provide us with a hypothesis how the bacteria can survive the initial phase of drug exposure.

Reference: Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism

TuberculosisWed, 26 Feb 2014 15:31:36 GMT
<![CDATA[Recommendation by the European Medicines Agency]]> Structure of TMC207/R207910

About a year after Bedaquiline (TMC207/R207910) had been approved by the FDA I have seen the news that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the "granting of a conditional marketing authorisation for the medicinal product Sirturo".

Reference: CHMP summary of positive opinion for Sirturo

TuberculosisFri, 20 Dec 2013 16:56:41 GMT