TMC207/R207910 results in five times higher activity in MDR-TB

Monday, October 27th, 2008 by hinrich

Structure of TMC207/R207910

In my last post I have highlighted the results from an early bactericidal activity study that was conducted in South Africa. Dr. Andreas Diacon of the University of Stellenbosch in South Africa Sunday has disclosed yesterday initial results from a new study at the 48th International Conference on Antimicrobials and Chemotherapy (ICAAC) in Washington DC.

This study was ondertaken with 150 patients carrying multi-drug resistant Mycobacterium tuberculosis (MDR-TB). Around half a million of patients worldwide suffer from MDR-TB. Due to the severe nature of MCR-TB, a cocktail of five different antibiotics is needed. One group of MDR-TB patients received a classic cocktail plus TMC207/R207910 while an equally large group received the same cocktail plus a placebo. In this study, TMC207/R207910 is being administered for 24 weeks.

Eight weeks after start of treatment the researchers have observed a complete removal of Mycobacterium tuberculosis form the sputum of patients for nearly half of the group (47 %) that received TMC207/R207910 as part of the cocktail. This result was achieved in only 8.7 % of the patients in the second group who received the classic cocktail with a placebo.

The findings that the drug seems to be well tolerated and initially shows effects against Mycobacterium tuberculosis that is five times higher as compared to the classic cocktail are very encouraging as Mycobacterium tuberculosis causes nearly nine million new cases of active disease and 2 million deaths each year.

Current estimates are that we will need at least two more years before TMC207/R207910 is ready for the market.

Posted in Tuberculosis

Activity in treatment-naive patients

Thursday, October 09th, 2008 by hinrich

Response in tuberculosis patients

First results from early bactericidal activity studies with TMC207/R207910 are being published. Rustomjee et al. have just published their article "Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis" in the journal Antimicrobial Agents and Chemotherapy.

The main findings of this phase IIa study with respect to TMC207/R207910 are the following: 75 treatment-naive patients with smear-positive pulmonary tuberculosis were given one of five different oral treatments. Three different concentrations of TMC207/R207910 (25 mg, 100 mg, and 400 mg), rifampin (600 mg), or isoniazid (300 mg) were given daily for 7 days. Sputum was collected daily and plated on selective agar plates to investigate how many Mycobacterium tuberculosis colonies still form. The researchers demonstrated significant bactericidal activity with the highest dose of TMC207/R207910 (400 mg) from day 4 onward. The effect was comparable in magnitude to those of isoniazid and rifampin over the same period.

The delayed onset of the effect of the compound in comparison to rifampin and isoniazid might be caused by the mechanism of action. As the compound works on the ATP synthase inhibiting the generation of new energy, it is tempting to conclude that after depletion of the available energy pool the bacteria start to become affected. However, this thinking remains speculation while we still have limited information.

The results are an encouraging read - especially when considering the closing comment of the authors in the introductory section of their article: "TMC207/R207910 is the first novel anti-TB compound to be studied in patients in nearly 4 decades."

You can read the abstract of the paper here.

Posted in Tuberculosis

Microarrays vs. next-gen sequencing

Thursday, October 02th, 2008 by hinrich

Affymetrix Workshop 2008

Scientists working with sequencing technologies are inspired by the potential that next-generation sequencing could offer. The hype that is being created around this potential reminds me a lot about the hype that was initially created when DNA microarrays were introduced as scientific tools. So, this is the question that is currently being asked: "The beginning of the end for microarrays"? This is the title of an article that was published recently in Nature Methods.
Last week I discussed the future of microarrays at an Affymetrix Workshop at Schering-Plough in Oss (Netherlands). Based on the discussions I have had, my current thoughts are: While next-generation sequencing offers the potential to identify true biological content (What DNA sequences are really detectable in an organism? | What information is really there that carries the basic plans of how to build proteins?), the use of the technology to tell us how that information is being used at a given moment will take much more fine-tuning.
Why that? False positives. The technology (like all technologies) makes mistakes. Due to the overwhelming amount of data that is being generated by next-generation sequencers, the raw data is typically not saved. Only the interpreted data (the sequence code, e.g. AGGTTCTTAGT...) is captured. At that moment one has no data about whether this sequence was actually present in the sample or whether alterations in the sequence were introduced by the lab procedures.
There is one way to remove false positives: Increasing the number of sequences (the "coverage") with the aim to conclude that sequences that are present only few times are false positives as opposed to sequences that are detected many times. However, this approach makes the following assumption: Given a certain coverage (say 50x), every sequence will be sequenced approximately 50 times on average. In other words, if there were to be regions of the genomic DNA that are always more often sequenced than other regions, we would not be able to remove false positives as we would need to arbitrarily define a threshold. Unfortunately, current technology does produce highly variable sequence coverage for different regions.
In other words: I think that we will see a drastic increase in the use of next-generation sequencing. This will lead to tons of sequence data for which suitable analysis techniques will be developed. This in turn will allow us to better define the true genetic information present in an organism. Being able to increase the accuracy of this information will allow us to screen with other tools (such as RTqPCR or DNA microarrays) what the biological function of these sequences are.

The PubMed entry for the paper "The beginning of the end for microarrays?" can be found here.

Posted in Molecular Profiling